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Adaptive immunity

The document discusses adaptive immunity and the specific immune response. It describes how adaptive immunity provides lifelong protective immunity through antigen-specific responses that are mediated by lymphocytes, including B cells, T cells, helper T cells, and killer T cells. Lymphocytes have antigen receptors like the B cell receptor and T cell receptor that provide specificity. The adaptive immune response develops over a person's lifetime through somatic recombination and clonal selection that generates a diverse repertoire of lymphocytes each with a unique receptor.

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Adaptive Immunity: Specific Immune Response (e.g., antibody) against a particular microorganism is an adaptive immune response. That is, it occurs during one’s lifetime as an adaptation to the presence of that particular organism. (specific means the ability to distinguish one organism from another) An adaptive immune response might provide lifelong protective immunity to a given pathogen. Specific immunity can be induced by a variety of substances. Things that targets of adaptive immunity are called ANTIGENS* * Things that induce an adaptive immune response are immunogens Antigen-specific responses are mediated by lymphocytes
Lymphocytes B Cells Plasma Cells T Cells Helper T Cells Killer T Cells Antibody production Signaling molecules Cytotoxic molecules
Lymphocyte Specificity Lymphocyte Lymphocyte antigen receptor (100 million different types per person) Foreign cell
Bone marrow for B cells Clonal Selection The somatic evolution of B and T cells populations Thymus for T cells XX XX Antigen binding in the bone marrow leads to B cell deletion (death). Strong antigen binding in the thymus leads to T cell deletion periphery clonal expansion Antigen binding in the periphery can lead to activation (other signals are required, too)
1* 3 4 2 The self/nonself discrimination (or tolerance) is “learned” in the soma *Numbers represent the 4 panels in the previous slide
TCR complex TCR -8 transmembrane protein -V,D,J segment are highly polymorphic. -TCR responsible for Ag recognition -CD3 responsible for signal transduction through ITAMs ITAMs ITAMs
Similarity between TCR and Ig Bind antigen Have variable region Constant region Each binding site is a heterodimer (composed of 2 different chains) TCRs act only as receptors Igs act as receptors and effector molecules (soluble antigen-binding molecules)
TCR • • αβ 95% of T lymph Ɣδ 5% ot peripheral T and NK Phenotype:DP or SP Site:thymus,LN,spleen Ag :processed and presented by MHCI or MHC II DN or CD8 Epidermis,epith of tounge,intestine Effector function; Th,Tcyt Can recognize unprocessed Ag without MHC presentation Protect the integrity of wound healing Cytolytic effect Produce Ɣ interferon
TCR Gene Rearrangements TCR gene rearrangment
TCR Gene Rearrangements
TCR Genes and Proteins
Alternative D region usage
heptamer J Spacers and nonamers not shown D D heptamer J CDR3
TCR Diversity
What is achieved by gene rearrangements and other mechanisms for the generation of diversity? 1. Relatively few gene segments can combine to make millions of different receptors (large repertoire) (i.e., 100s of gene segments can be assembled to make millions of variable regions for Igs and TCRs). 2. Different cells can have different antigen receptors. 3. Somatic progeny of a cell with a gene rearrangement will inherit the gene rearrangement and thus inherit the antigen recognition specificity of the parent cell.
MHC restriction T cell system is heavily biased towards recognizing peptides bound to selfMHC that result in positive selection in the thymus that favors the survival of developing T whose TCRs have the potential to recognize peptides presented by self MHC.
One specificity per T cell (one antigen and one restriction specificity combination ). For example, let’s look at MHC class I restricted T cells Class I β 2 microglobulin is not encoded in MHC MHCa (HLAa) Ba Ca Aa 6 possible restriction specificities per individual Anti-X restricted to Ba Bb Cb Ab MHCb (HLAb) Anti-X restricted to Bb Anti-X restricted to Ca Pairs of chromosomes in each cell so each cell has two MHC loci. Within each locus are B, C and A genes encoding MHC class I proteins (polygeneic). Because MHC is polymorphic, it is likely that the alleles for B, C and A are different. Anti-X restricted to Cb Anti-X restricted to Aa X represents an antigen (e.g., a virus) however, it is not likely that all the T cells recognize the same peptide derived from X Anti-X restricted to Ab Within an individual there will be many different T cell clones, each with one restriction specificity, responding to various peptides derived from the same antigen (or pathogen). The more common HLA nomenclature is B*0702 Cw*0203 A*0209
The example on the previous slide is for MHC class I. However, the principle of one restriction specificity and one antigen specificity per T cell is exactly the same for MHC class II restricted T cells. the antigen and the allele-specific determinants of MHC as separate entities but recognizes a new antigenic determinant formed by the combination of antigen (peptide) and MHC.
T-cell ontogeny T cell development is defined by changes in expression of three surface proteins: TCR/CD3, CD4 and CD8 CD4-CD8- (DN) CD4+CD8+ (DP) CD4-CD8+ OR CD4+CD8- (SP)
Positive selection for self MHC restriction Negative selection are anti-self MHC restriction
Thymic selection of T cells cortico-medullary junction cortex subcapsular region medulla tingible body macrophage interdigitating cell thymocyte thymic epithelial cell macrophage blast cell POSITIVE SELECTION Interaction with MHC class I or MHC class II on cortical epithelium cortex medulla NEGATIVE SELECTION Interaction with MHC class I or MHC class II + self peptide (dendritic cells, macrophages)
MHC restriction T cell system is heavily biased towards recognizing peptides bound to selfMHC that result in positive selection in the thymus that favors the survival of developing T whose TCRs have the potential to recognize peptides presented by self MHC.
Avidity: apparent affinity bet TCR and (MHC/peptide complex) which depends on (occupancy of TCR by MHC) High occupancy =negative selection by apoptosis Moderate occupancy =positive selection =thymocyte growth and maturation low occupancy =low avidity=no signal=negative selection by deletion (apoptosis)or anergy
Avidity hypothesis Not differential signaling No positive selection Positive selection No negative selection nothing here so this cannot be correct No positive selection Negative selection Positive and negative selection can be successful if each is governed by different avidities (e.g., low avidity for positive selection; high avidity for negative selection) Positive and negative selection occur in the presence of selfpeptides but in the absence of foreign-peptides. Changing from self-peptide to foreign will change binding affinity of the TCR for MHC + peptide. Thus, a TCR with low avidity binding for self peptide + MHC will have high avidity binding for some foreign peptide + MHC.
T cells bind to the combination of foreign peptide* and MHC. T cells cannot bind foreign peptide alone nor MHC alone. T cell T cell T cell peptide TCR MHC TCR binding? Yes No No *derived from foreign protein by antigenprocessing
In the thymus T cells undergo positive and negative selection: Positive selection - selects T cells with T cell receptors (TCRs) that are able to interact with self MHC class I and II molecules on thymic epithelial cells Negative selection - deletes cells that recognise self antigens expressed in conjunction with MHC class I or II molecules on thymic dendritic cells or macrophages. If the interaction is of a high affinity, the T cells will be deleted, if low affinity the T cells may escape negative selection.
How do T cells recognize antigens?
Nominal antigens & superantigens Nominal antigens Superantigens Require processing to peptides Not processed TcRα and β chains are involved in recognition Only TcR β chain involved in recognition <1 in 105 T cells recognise each peptide 2-20% of T cells recognise each superantigen Recognition restricted by an MHC class I or II molecule Presented by almost any MHC class II molecule Almost all proteins can be nominal antigens Very few antigens are superantigens Suggests a strikingly different mechanism of antigen presentation & recognition.
Superantigens T cell e.g. Staphylococcal enterotoxins Toxic shock syndrome toxin I (TSST-1) Staphylococcal enterotoxins SEA, SEB, SEC, SED & SEE Do not induce adaptive responses, but trigger a massive burst of cytokines that may cause fever, systemic toxicity & immune suppression Severe food poisoning Toxic shock syndrome Vβ Vα TcR from MHC A haplotype Class II from MHC A to Z haplotypes APC
A big picture: How do T cells recognize antigens? MHC molecule TCR
Tcell activation (3 signals)
Signal 1 : TCR recognises MHC/antigen complex (TCR complex contains CD3, CD45 etc…) T cell activation Signal 2 : Costimulation 1-T cell CD28 binds to B7 family (CD80, CD86), 2- CD40 and CD 40 L Signal 3 : T cell Activation by an Activated APC(IL12,IL1,IL6) DO NOT FORGET Co-Receptors RESULT New gene transcription (IL-2, IL-2r….) Proliferation & expansion of the specific clone
Signal 1 :TCR recognises MHC/antigen complex+coreceptors
T cell Activation by an Activated APC IL-1 IL-6 IL-12 CD28 “Signal 3” B7 CD4 ++ CD4 T cell T cell LPS T Cell Receptor “Signal 2” TLR4 “Signal 1” Peptide MHC II Antigen Presenting Cell (APC )
T cell Activation by an Activated APC IL-1 IL-6 IL-12 IL-12 Receptor CD28 “Signal 3” B7 CD4 ++ CD4 T cell T cell LPS T Cell Receptor “Signal 2” TLR4 “Signal 1” Peptide MHC II Signal 1: Specificity Signal 2: Activation Signal 3: Differentiation Antigen Presenting Cell (APC)
The 2-Signal Model of Lymphocyte Activation CTLA-4 B7 (CD80/86) B7 (CD80/86) APC CD28 TCR MHC ↓Activation ↑Activation Recognition II CD2 CD58 (LFA3) ↑Activation CD40 Adhesion CD40L CD4 + T CELL T Cell
The Immunological Synapse: Co-Receptors For T cells: co-receptors bind to MHC of MHCAg peptide complex CD4: MHC II  CD8: MHC I  Co-binding of TCR and co-receptor leads to lowered threshold for activation Recruitment of Lck to TCR through association with CD4 or CD8 cytoplasmic tail B cell co-receptor: CD19, CD21, CD81 complex CD21 recognizes activated complement  CD19 constitutively associated 
T Cell Recognition
Molecular Interactions of Helper T Cells and APC CD4+ T Cell CTLA-4 CD28 p56 lck CD3 CD40L Cα C β V α CD2 ζ ζη η γδ ε TCR Vβ CD45 LFA-1 VLA-1 peptide B7 B7 CD80/CD86 CD4 CD40 MHC II APC/ B cell LFA-3 ICAM-1
Antigen presentation - T cells are co-stimulated Signal 1 antigen & antigen receptor Th APC ACTIVATION Signal 2 B7 family members (CD80 & CD86) CD28 Costimulatory molecules are expressed by most APC including dendritic cells, monocytes, macrophages, B cells etc., but not by cells that have no immunoregulatory functions such as muscle, nerves, hepatocytes, epithelial cells etc.
T helper cells costimulate B cells Two - signal models of activation Signal 1 antigen & antigen receptor B Y YY CD40 MHC class II and peptide ACTIVATION Th Signal 2 - T cell help T cell antigen receptor Co-receptor (CD4) CD40 Ligand (CD154)
Mechanism of co-stimulation in T cells Low affinity IL-2 receptor IL-2 Antigen 1 IL-2 IL-2Rα IL-2Rα Resting T cells Express IL-2 receptorβ and γ chains but no α chain or IL-2 Signal 1 NFAT binds to the promoter of of the α chain gene of the IL-2 receptor. The α chain converts the IL-2R to a high affinity form
Arming of effector T cells Clonal selection and differentiation APC T IL-2 Effector T cell Activation of NAÏVE T cells by signal 1 and 2 is not sufficient to trigger effector function, but….. the T cell will be activated to proliferate and differentiate under the control of autocrine IL-2 to an effector T cell. These T cells are ARMED How can this cell give help to, or kill cells, that express low levels of B7 family costimulators?
Effector function or Anergy? Clonally selected, proliferating and differentiated T cell i.e. ARMED sees antigen on a B7 -ve epithelial cell IL-2 The effector programme of the T cell is activated without costimulation Armed Effector T cell Armed Effector T cell This contrasts the situation with naïve T cells, which are anergised without costimulation Naïve T cell CD28 TcR Co-receptor Kill Epithelial cell Epithelial cell Epithelial cell
Anergy Antigen Naïve T cell 1 Signal 1 only IL-2 IL-2Rα Epithelial cell Self peptide epitopes presented by a non-classical APC e.g. an epithelial cell The T cell is unable to produce IL-2 and therefore is unable to proliferate or be clonally selected. in the absence of signal 2 causes antigen specificT cell unresponsiveness.
Antigen TCR TH2 activation, for example Plasma cell The two signal model for lymphocyte activation (antigen alone is insufficient) Here, signal 2 is TCRmediated, antigen specific recognition; not shown. (see similar slide later) (Mature dendritic cell) (Mature naive T cell) Proliferation and differentiation of the T cell to effector function (Armed effector T cell) Proliferation and differentiation of the B cell to effector function Memory B cell B cell activation, for example Signal 1 comes from recognition of antigen Signal 2 comes from another (activated) cells
TCR signaling
TCR complex TCR -8 transmembrane protein -V,D,J segment are highly polymorphic. -TCR responsible for Ag recognition -CD3 responsible for signal transduction through ITAMs ITAMs ITAMs
T Cell Activation: Early Steps Prior to cell-cell contact, dephosphorylation predominates: ITAMs unphosphorylated CD45 phosphatase complexes with CD4 Maintains activationcompetent stateremoval of Cterminal of Lck From Nel, J. Allerby, Clin Immunol, 2002
B Menu F
TCR Signaling: CD4 enhancement, Lck activation and recruitment and activation of Zap-70.
TCR signaling PLCγ1 CD4 CD28 Zap70 Lck Fyn Tec (PMA) IP3 + DAG Ca++ Lck Shc Grb2 PIP2 (ION) CD45 SOS Ras PKC MAPK calcineurin NFκB NFAT activation Lymphokines gene expression PTK
Figure 6-16
T cell differentiation
Effector T Cells Composed of three kinds of cells: CD8+ TC cells cells CD8 TH 1 & TH 2 cells  T H1 & T H2 cells  Characterized by: Less Stringent activation requirements CD28B7 interaction NOT necessary for activation  Increased expression of cell-adhesion molecules    increased expression of CD2 & integrin LFA1 Production of effector molecules:
T Helper
T cell differentiation T cells are heterogenous Different stimulus leads to differentiation of different types of response Th1 - very inflammatory: fight bacteria etc Th2 - less inflammatory: fight parasites etc Th3 - anti-inflammatory: maintain balance?
T helper Cell Differentiation • Type 1 response Th1 IFNγ TNF-b IL 2 • immunity to mycobacteria • inflammation • rheumatoid arthritis, diabetes Th0 Th2 IL4 IL13 IL10 • Type 2 response • IgE antibody responses • Immunity to some parasites • allergic diseases
γ IFN,TNF IL2 + + IL2 + TH1 IL12/IL6 + APC pathogen local microenvironment CD40 TH0 B7 TH1 IFN γ - - IL4 IL2 + TH2 + IL10 TH2 IL4/IL10 - + IL4
B Menu F
Cytotoxic T
Focus: Cytotoxic T cells Cytotoxic T Generated by Immune activation of TC cell precursors Have lytic capabilities Play critical role in recognition of altered self cells MHC I restricted (generally)  All nucleated cells in body express MHC I molecules
Generation of Effector Cytotoxic T cells Cytotoxic T Requires three specific signals:  Signals for Activation 1-Primary antigen specific TCR(CD8+)-Ag-MHC I interaction  2-Co-stimulatory CD28-B7 interaction    (may not be necessary for Memory TC cell precursors ) Signals for Proliferation & Differentiation 3-Signal from IL-2 interaction with high-affinity IL-2 Receptor  Generally T cell precursors (CTL-P’s) need IL-2 produced C from TH1 cells for proliferation   Memory TC cell precursors may produce enough IL-2 to self-proliferation
Cytotoxic T cell activation
Figure 14-2
Cytotoxic cell’s Granule Cytotoxic T attach steps Mediated Homicide 1) Conjugate formation 2) Membrane attack 3) TC cell dissociation 4) Target cell obliteration (destruction)
Figure 14-6
Cytotoxic T cell 1-Granules Mediated pathway. 2- Fas-FasL pathway. Cytotoxic T cell’s Granule Mediated Homicide 1-Granules Mediated pathway 1) Conjugate formation Recognition: TCR-Ag-MHC I interaction  Embrace: LFA-1 receptor (T cell) binds to ICAM’s C on target cell membrane  2) Membrane attack 3) TC cell dissociation 4) Target cell obliteration (destruction)
1) Conjugate formation 2)Cytotoxic Tattack Granule Mediated Homicide Membrane cell’s  Cytoplasmic rearrangement   Brings Golgi and storage granules into closer proximity to target cell Granule Secretion (exocytosis)  Perforin - 65kDa monomer    Undergoes conformational change upon contact with target cell membrane which exposes amphipathic domain, enabling insertion into membrane. Once in membrane perforins polymerize and create 5-20nm pores (w/Ca2+). Granzyme 3) TC cell dissociation 4) Target cell obliteration (destruction)
Figure 14-9a: Perforin pore formation in target cell membrane
Figure 14-9b: EM of perforin pores in target cell membrane
Cytotoxic T cell 1-Granules Mediated pathway. 2- Fas-FasL pathway. 1-Granules Mediated pathway 1) Conjugate formation 2) Membrane attack Cytoplasmic rearrangement  Granule Secretion (exocytosis)  Perforin - 65kDa monomer  Granzyme    Binds to mannose 6-phosphate receptor and internalized into target cell. The Perforin pores allow the Granzyme to exit internalized vesicles. Once inside cytoplasm of target cell, initiates reaction cascade culminating in activation of endonucleases which in turn digest DNA into oligomers of ~200bp (typical of apoptosis). 3) TC cell dissociation
Figure 14-11: Caspase Cascade
Cytotoxic T cell’s Fas Ligand Mediated Homicide Fas Transmembrane protein  Member of the TNF-receptor family  Can deliver death signal when crosslinked with its natural ligand   Natural ligand is a TNF called Fas ligand (FasL) 2) FasL  Found on the membrane of TC cells  Interaction with Fas protein triggers target cell apoptosis 3) Fas-FasL interaction  elucidated by experiments with perforin
Cell Death by Apoptosis Caspase  Family of cysteine proteases which cleave after Asp residue  Normally present in cell as inactive proenzymes “procaspases”  >12 caspases with different specificity have been identified  Cleavage of procaspase produces an active initiator caspase, which in turn cleaves other caspases.  Both Granule and Fas mediated apoptotic signaling induces the caspase cascade (Fig14-11) by activating Procaspase-8.  Results in “systematic” disassembly of the cell
Cell Organization of C-MER Cytotoxic cells Cells with direct cytotoxic activity:  Antigen specific   + CD8+ Cytotoxic T cells (TC C cells or CTL’s) Cytotoxic T cells (T cells or CTL’s) Nonspecific Natural Killer Cells (NK cells) Natural Killer Cells (NK cells)  Macrophages  Cells that mediate the delayed-type hypersensitivity reactions (DTHR):  CD4+ TH cells TH1 cells TH1 cells T 2 cells  T H2 cells H 
Tof T-cell Effector Molecules cell functions Functions Mediate target-cell destruction by TC cells:    Fas ligand (membrane-bound) perforins (soluble) granzimes (soluble) TC cell Promote macrophage activity:    TNF-β (soluble & membrane-bound) INF-γ (soluble) GM-CSF (soluble) T H1 TH2 Play role in B-cell activation by TH2 cells:   CD40 (membrane bound) IL-4, IL-5, IL-6 (soluble)
CTL deal with antigens in the cytoplasm by killing the cells that present the antigen TH1 deals mostly with antigen in macrophage vesicles by activating the macrophages. That is, antigens that have been phagocytized. Activated macrophages are more aggressive in killing phagocytized material and they release toxic compounds into the local environment. TH2 deals with antigens that were bound to a B cell’s BCRs (extracellular antigens) and internalized (into vesicles). They activate B cells for antibody secretion.
For antigens to be recognized by CTLs, they must be presented in association with MHC class I. For antigens to be recognized by TH1 or TH2, they must be presented in association with MHC class II. Therefore, CTLs are interested in proteins synthesized inside a cell whereas TH1 and TH2 are interested in proteins that were synthesized outside of a cell but were brought into the cell in vesicles
The Control of Activated CD4+ T Cells by Regulatory T cells NKT cells/ CD4+CD25+ cells CD4+CD25- cells Apoptosis peptide/APC (- ) TH1 CD4+ cells IL-12/ IFN-γ (- ) IL-10 (- ) IL-4 Resting CD4 T cells IFN-γ Activated CD4 T cells (- ) TH2 CD4+ cells Regulatory immunity CD4/CD8 interactions CD8 or CD4 suppressor effector CD8 or CD4 suppressor precursor L. Chess 2002
Regulatory T cell Suppressor Cell Natural Treg Regulatory cells RegulatoryTT Cell Subsets Murine Markers CD8+ CD4+, CD25+ CTLA-4+, GITR+, Foxp3+ (intracellular) Adaptive Treg CD4+, CD25 -, Foxp3Tr1 CD4+, CD45Rb lo Th3 CD4+, CD45Rb lo Invariant NKT cell Invariant TCRα (Vα14-Jα281), CD4+, CD8-, NK1.1+ Proposed Mechanisms of Inhibition Recogn ition of Qa-1:peptide on activated CD4+ T cells → induction of cytotoxicity Cell-contact dependen t but not antigen-specific; Ligation of B7 on effector cells; IL-2 sequestration; CTLA-4 interaction with IDO → tolerogenic DCs; IL-10 & TGF-beta production Cell-contact dependen t but not antigen-specific inhibition Cell-contact independen t; IL-10 & IL-4 secretion Cell-contact independen t; TGF-beta secretion CD1d:glycolipid complex recogn ition; IL-10 secretion
Natural Killer (NK) Cells Functions 1-showed significant lysis of tumor cells. Compose 5-10% of recirculating lymphocyte population Involved in immune defense against virus and tumors 2-Play important role in immune regulation:  Influence both adaptive and innate immunity via cytokine production/excretion:  INFγ:  Affects phagocytic and microbial activities of macrophages  Influences T 1 cells vs T 2 cells commitment of development H H 3-First line of defense in viral infections  Number of NK cells peaks ~3 days after infection
Comparison between NK and T Cells Similarities   Common early progenitor (Lymphoid progenitor) Express some common membrane markers:    CD2 75 kDa β subunit of the IL-2 receptor *CD16 Receptor for Fc region of IgG Differences   NK cells do not develop exclusively in the thymus Do not undergo rearrangement of receptor genes
Comparison of NK and T-cell Assassination Mechanism Similar to processes employed by CTL’s    Express FasL on membrane surface Contain Granules of perforin and granzimes Target cell degradation occurs via perforins and granzymes Different from CTL’s cytotoxicity     NK always cytotoxic, do not need to be activated to produce granules Do not express Ag specific T-cell receptors or CD3 Recognition of target cells is NOT MHC restricted NK immune response generates no immunological memory  No greater immune response upon secondary infection
Natural Killer (NK) Cells Express inhibition and activation receptors on cells surface  Many inhibition and many activation receptors create an opposingsignal model.  The balance between the opposing signals is believed to enable NK to differential between healthy and infected cells (Fig 14-14) Additional NK activator signals can be delivered by soluble factors  TNF-α, IL-12, and IL-15 NK cells may target cells that produce aberrant MHC expression  Many virus-infected and tumor cells have reduced MHC expression
NK Cells Inhibitor-Receptor Superfamily C-type-lectin-inhibitory receptor (CLIR)  In humans: CD94/NKG2 - disulfide bonded heterodimer of two glycoproteins  Recognizes HLA-E on potential target cells   HLA-E serves as indicator of overall level of MHC I biosynthesis Thus CD94/NKG2 are not specific for specific HLA allele Killer-cell-inhibitory receptors (KIR)  A group of Ig-superfamily-inhibitory receptors (ISIR)   more than 50 family members have been found Specific for one or more of polymorphic HLA products Inhibitory receptors have veto power over activation receptors   Thus, cells expressing normal levels of MHC I receptors tend to escape all forms of NK assassination. Thus cells that lack normal MHC I expression = lack of normal self expression DIE!!!
Fig. 14-14: Opposing-signals model of cytotoxic activity
What is NKT Cells? Immunology Today November 2000 Vol21 No.11 573
Characteristics  Express both T cell receptors and NK1.1 receptors — hence its name.  Respond to glycolipid antigens presented by CD1d  CD1 restricted rather than MHC restricted  CD4+ or Double negative, in mice  Secrete large amounts of either IFN-γ, IL-4, TNF  Lack immunological memory
1.Control of infection Current Biology Vol 15 No 11,2005
2.Bridging innate and acquired immunity VOLUME 4 NUMBER 12 DECEMBER 2003 NATURE IMMUNOLOGY
Models of Memory Lymphocyte Development Ag + Co-stimulation Effector Cell CLASSIC THEORY Activated cell in Environment X Ag Naïve cell Activated cell in Environment Y Memory Cell Ag Effector Cell Precursor KLINMAN LINEAGE HYPOTHESIS Effector Cell Ag Ag Memory Cell Precursor Memory Cell Effector Cell
Ag + Costimulation Ag Apoptotic Death 95 to 99% 1 to 5% Naïve Cell Activated cell Effector Cell LINEAR DIFFERENTIATION MODEL Ag + Costimulation Memory Cell Activated cell Activated/Effector Cell Ag Effector Cell Ag Naïve Cell Memory Cell Memory Cell Memory Cell DIMINISHING POTENTIAL MODEL

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Adaptive immunity

  • 2.
    Adaptive Immunity: Specific ImmuneResponse (e.g., antibody) against a particular microorganism is an adaptive immune response. That is, it occurs during one’s lifetime as an adaptation to the presence of that particular organism. (specific means the ability to distinguish one organism from another) An adaptive immune response might provide lifelong protective immunity to a given pathogen. Specific immunity can be induced by a variety of substances. Things that targets of adaptive immunity are called ANTIGENS* * Things that induce an adaptive immune response are immunogens Antigen-specific responses are mediated by lymphocytes
  • 3.
    Lymphocytes B Cells Plasma Cells TCells Helper T Cells Killer T Cells Antibody production Signaling molecules Cytotoxic molecules
  • 4.
    Lymphocyte Specificity Lymphocyte Lymphocyte antigenreceptor (100 million different types per person) Foreign cell
  • 5.
    Bone marrow for Bcells Clonal Selection The somatic evolution of B and T cells populations Thymus for T cells XX XX Antigen binding in the bone marrow leads to B cell deletion (death). Strong antigen binding in the thymus leads to T cell deletion periphery clonal expansion Antigen binding in the periphery can lead to activation (other signals are required, too)
  • 6.
    1* 3 4 2 The self/nonself discrimination(or tolerance) is “learned” in the soma *Numbers represent the 4 panels in the previous slide
  • 7.
    TCR complex TCR -8 transmembraneprotein -V,D,J segment are highly polymorphic. -TCR responsible for Ag recognition -CD3 responsible for signal transduction through ITAMs ITAMs ITAMs
  • 8.
    Similarity between TCR andIg Bind antigen Have variable region Constant region Each binding site is a heterodimer (composed of 2 different chains) TCRs act only as receptors Igs act as receptors and effector molecules (soluble antigen-binding molecules)
  • 10.
    TCR • • αβ 95% of Tlymph Ɣδ 5% ot peripheral T and NK Phenotype:DP or SP Site:thymus,LN,spleen Ag :processed and presented by MHCI or MHC II DN or CD8 Epidermis,epith of tounge,intestine Effector function; Th,Tcyt Can recognize unprocessed Ag without MHC presentation Protect the integrity of wound healing Cytolytic effect Produce Ɣ interferon
  • 11.
    TCR Gene Rearrangements TCRgene rearrangment
  • 12.
  • 13.
    TCR Genes andProteins
  • 14.
  • 15.
    heptamer J Spacers and nonamersnot shown D D heptamer J CDR3
  • 16.
  • 17.
    What is achievedby gene rearrangements and other mechanisms for the generation of diversity? 1. Relatively few gene segments can combine to make millions of different receptors (large repertoire) (i.e., 100s of gene segments can be assembled to make millions of variable regions for Igs and TCRs). 2. Different cells can have different antigen receptors. 3. Somatic progeny of a cell with a gene rearrangement will inherit the gene rearrangement and thus inherit the antigen recognition specificity of the parent cell.
  • 18.
    MHC restriction T cellsystem is heavily biased towards recognizing peptides bound to selfMHC that result in positive selection in the thymus that favors the survival of developing T whose TCRs have the potential to recognize peptides presented by self MHC.
  • 19.
    One specificity perT cell (one antigen and one restriction specificity combination ). For example, let’s look at MHC class I restricted T cells Class I β 2 microglobulin is not encoded in MHC MHCa (HLAa) Ba Ca Aa 6 possible restriction specificities per individual Anti-X restricted to Ba Bb Cb Ab MHCb (HLAb) Anti-X restricted to Bb Anti-X restricted to Ca Pairs of chromosomes in each cell so each cell has two MHC loci. Within each locus are B, C and A genes encoding MHC class I proteins (polygeneic). Because MHC is polymorphic, it is likely that the alleles for B, C and A are different. Anti-X restricted to Cb Anti-X restricted to Aa X represents an antigen (e.g., a virus) however, it is not likely that all the T cells recognize the same peptide derived from X Anti-X restricted to Ab Within an individual there will be many different T cell clones, each with one restriction specificity, responding to various peptides derived from the same antigen (or pathogen). The more common HLA nomenclature is B*0702 Cw*0203 A*0209
  • 20.
    The example onthe previous slide is for MHC class I. However, the principle of one restriction specificity and one antigen specificity per T cell is exactly the same for MHC class II restricted T cells. the antigen and the allele-specific determinants of MHC as separate entities but recognizes a new antigenic determinant formed by the combination of antigen (peptide) and MHC.
  • 21.
    T-cell ontogeny T celldevelopment is defined by changes in expression of three surface proteins: TCR/CD3, CD4 and CD8 CD4-CD8- (DN) CD4+CD8+ (DP) CD4-CD8+ OR CD4+CD8- (SP)
  • 22.
    Positive selection forself MHC restriction Negative selection are anti-self MHC restriction
  • 23.
    Thymic selection ofT cells cortico-medullary junction cortex subcapsular region medulla tingible body macrophage interdigitating cell thymocyte thymic epithelial cell macrophage blast cell POSITIVE SELECTION Interaction with MHC class I or MHC class II on cortical epithelium cortex medulla NEGATIVE SELECTION Interaction with MHC class I or MHC class II + self peptide (dendritic cells, macrophages)
  • 24.
    MHC restriction T cellsystem is heavily biased towards recognizing peptides bound to selfMHC that result in positive selection in the thymus that favors the survival of developing T whose TCRs have the potential to recognize peptides presented by self MHC.
  • 25.
    Avidity: apparent affinity betTCR and (MHC/peptide complex) which depends on (occupancy of TCR by MHC) High occupancy =negative selection by apoptosis Moderate occupancy =positive selection =thymocyte growth and maturation low occupancy =low avidity=no signal=negative selection by deletion (apoptosis)or anergy
  • 26.
    Avidity hypothesis Not differentialsignaling No positive selection Positive selection No negative selection nothing here so this cannot be correct No positive selection Negative selection Positive and negative selection can be successful if each is governed by different avidities (e.g., low avidity for positive selection; high avidity for negative selection) Positive and negative selection occur in the presence of selfpeptides but in the absence of foreign-peptides. Changing from self-peptide to foreign will change binding affinity of the TCR for MHC + peptide. Thus, a TCR with low avidity binding for self peptide + MHC will have high avidity binding for some foreign peptide + MHC.
  • 27.
    T cells bindto the combination of foreign peptide* and MHC. T cells cannot bind foreign peptide alone nor MHC alone. T cell T cell T cell peptide TCR MHC TCR binding? Yes No No *derived from foreign protein by antigenprocessing
  • 28.
    In the thymusT cells undergo positive and negative selection: Positive selection - selects T cells with T cell receptors (TCRs) that are able to interact with self MHC class I and II molecules on thymic epithelial cells Negative selection - deletes cells that recognise self antigens expressed in conjunction with MHC class I or II molecules on thymic dendritic cells or macrophages. If the interaction is of a high affinity, the T cells will be deleted, if low affinity the T cells may escape negative selection.
  • 29.
    How do Tcells recognize antigens?
  • 30.
    Nominal antigens &superantigens Nominal antigens Superantigens Require processing to peptides Not processed TcRα and β chains are involved in recognition Only TcR β chain involved in recognition <1 in 105 T cells recognise each peptide 2-20% of T cells recognise each superantigen Recognition restricted by an MHC class I or II molecule Presented by almost any MHC class II molecule Almost all proteins can be nominal antigens Very few antigens are superantigens Suggests a strikingly different mechanism of antigen presentation & recognition.
  • 31.
    Superantigens T cell e.g. Staphylococcal enterotoxins Toxicshock syndrome toxin I (TSST-1) Staphylococcal enterotoxins SEA, SEB, SEC, SED & SEE Do not induce adaptive responses, but trigger a massive burst of cytokines that may cause fever, systemic toxicity & immune suppression Severe food poisoning Toxic shock syndrome Vβ Vα TcR from MHC A haplotype Class II from MHC A to Z haplotypes APC
  • 32.
    A big picture: Howdo T cells recognize antigens? MHC molecule TCR
  • 33.
  • 34.
    Signal 1 :TCR recognises MHC/antigen complex (TCR complex contains CD3, CD45 etc…) T cell activation Signal 2 : Costimulation 1-T cell CD28 binds to B7 family (CD80, CD86), 2- CD40 and CD 40 L Signal 3 : T cell Activation by an Activated APC(IL12,IL1,IL6) DO NOT FORGET Co-Receptors RESULT New gene transcription (IL-2, IL-2r….) Proliferation & expansion of the specific clone
  • 35.
    Signal 1 :TCRrecognises MHC/antigen complex+coreceptors
  • 36.
    T cell Activationby an Activated APC IL-1 IL-6 IL-12 CD28 “Signal 3” B7 CD4 ++ CD4 T cell T cell LPS T Cell Receptor “Signal 2” TLR4 “Signal 1” Peptide MHC II Antigen Presenting Cell (APC )
  • 37.
    T cell Activationby an Activated APC IL-1 IL-6 IL-12 IL-12 Receptor CD28 “Signal 3” B7 CD4 ++ CD4 T cell T cell LPS T Cell Receptor “Signal 2” TLR4 “Signal 1” Peptide MHC II Signal 1: Specificity Signal 2: Activation Signal 3: Differentiation Antigen Presenting Cell (APC)
  • 38.
    The 2-Signal Modelof Lymphocyte Activation CTLA-4 B7 (CD80/86) B7 (CD80/86) APC CD28 TCR MHC ↓Activation ↑Activation Recognition II CD2 CD58 (LFA3) ↑Activation CD40 Adhesion CD40L CD4 + T CELL T Cell
  • 39.
    The Immunological Synapse: Co-Receptors ForT cells: co-receptors bind to MHC of MHCAg peptide complex CD4: MHC II  CD8: MHC I  Co-binding of TCR and co-receptor leads to lowered threshold for activation Recruitment of Lck to TCR through association with CD4 or CD8 cytoplasmic tail B cell co-receptor: CD19, CD21, CD81 complex CD21 recognizes activated complement  CD19 constitutively associated 
  • 40.
  • 41.
    Molecular Interactions ofHelper T Cells and APC CD4+ T Cell CTLA-4 CD28 p56 lck CD3 CD40L Cα C β V α CD2 ζ ζη η γδ ε TCR Vβ CD45 LFA-1 VLA-1 peptide B7 B7 CD80/CD86 CD4 CD40 MHC II APC/ B cell LFA-3 ICAM-1
  • 42.
    Antigen presentation -T cells are co-stimulated Signal 1 antigen & antigen receptor Th APC ACTIVATION Signal 2 B7 family members (CD80 & CD86) CD28 Costimulatory molecules are expressed by most APC including dendritic cells, monocytes, macrophages, B cells etc., but not by cells that have no immunoregulatory functions such as muscle, nerves, hepatocytes, epithelial cells etc.
  • 43.
    T helper cellscostimulate B cells Two - signal models of activation Signal 1 antigen & antigen receptor B Y YY CD40 MHC class II and peptide ACTIVATION Th Signal 2 - T cell help T cell antigen receptor Co-receptor (CD4) CD40 Ligand (CD154)
  • 44.
    Mechanism of co-stimulationin T cells Low affinity IL-2 receptor IL-2 Antigen 1 IL-2 IL-2Rα IL-2Rα Resting T cells Express IL-2 receptorβ and γ chains but no α chain or IL-2 Signal 1 NFAT binds to the promoter of of the α chain gene of the IL-2 receptor. The α chain converts the IL-2R to a high affinity form
  • 45.
    Arming of effectorT cells Clonal selection and differentiation APC T IL-2 Effector T cell Activation of NAÏVE T cells by signal 1 and 2 is not sufficient to trigger effector function, but….. the T cell will be activated to proliferate and differentiate under the control of autocrine IL-2 to an effector T cell. These T cells are ARMED How can this cell give help to, or kill cells, that express low levels of B7 family costimulators?
  • 46.
    Effector function orAnergy? Clonally selected, proliferating and differentiated T cell i.e. ARMED sees antigen on a B7 -ve epithelial cell IL-2 The effector programme of the T cell is activated without costimulation Armed Effector T cell Armed Effector T cell This contrasts the situation with naïve T cells, which are anergised without costimulation Naïve T cell CD28 TcR Co-receptor Kill Epithelial cell Epithelial cell Epithelial cell
  • 47.
    Anergy Antigen Naïve T cell 1 Signal 1 only IL-2 IL-2Rα Epithelial cell Selfpeptide epitopes presented by a non-classical APC e.g. an epithelial cell The T cell is unable to produce IL-2 and therefore is unable to proliferate or be clonally selected. in the absence of signal 2 causes antigen specificT cell unresponsiveness.
  • 48.
    Antigen TCR TH2 activation, for example Plasmacell The two signal model for lymphocyte activation (antigen alone is insufficient) Here, signal 2 is TCRmediated, antigen specific recognition; not shown. (see similar slide later) (Mature dendritic cell) (Mature naive T cell) Proliferation and differentiation of the T cell to effector function (Armed effector T cell) Proliferation and differentiation of the B cell to effector function Memory B cell B cell activation, for example Signal 1 comes from recognition of antigen Signal 2 comes from another (activated) cells
  • 49.
  • 50.
    TCR complex TCR -8 transmembraneprotein -V,D,J segment are highly polymorphic. -TCR responsible for Ag recognition -CD3 responsible for signal transduction through ITAMs ITAMs ITAMs
  • 51.
    T Cell Activation:Early Steps Prior to cell-cell contact, dephosphorylation predominates: ITAMs unphosphorylated CD45 phosphatase complexes with CD4 Maintains activationcompetent stateremoval of Cterminal of Lck From Nel, J. Allerby, Clin Immunol, 2002
  • 53.
  • 54.
    TCR Signaling: CD4 enhancement,Lck activation and recruitment and activation of Zap-70.
  • 55.
    TCR signaling PLCγ1 CD4 CD28 Zap70 Lck Fyn Tec (PMA) IP3+ DAG Ca++ Lck Shc Grb2 PIP2 (ION) CD45 SOS Ras PKC MAPK calcineurin NFκB NFAT activation Lymphokines gene expression PTK
  • 56.
  • 57.
  • 58.
    Effector T Cells Composedof three kinds of cells: CD8+ TC cells cells CD8 TH 1 & TH 2 cells  T H1 & T H2 cells  Characterized by: Less Stringent activation requirements CD28B7 interaction NOT necessary for activation  Increased expression of cell-adhesion molecules    increased expression of CD2 & integrin LFA1 Production of effector molecules:
  • 60.
  • 61.
    T cell differentiation Tcells are heterogenous Different stimulus leads to differentiation of different types of response Th1 - very inflammatory: fight bacteria etc Th2 - less inflammatory: fight parasites etc Th3 - anti-inflammatory: maintain balance?
  • 62.
    T helper CellDifferentiation • Type 1 response Th1 IFNγ TNF-b IL 2 • immunity to mycobacteria • inflammation • rheumatoid arthritis, diabetes Th0 Th2 IL4 IL13 IL10 • Type 2 response • IgE antibody responses • Immunity to some parasites • allergic diseases
  • 63.
  • 65.
  • 67.
  • 68.
    Focus: Cytotoxic Tcells Cytotoxic T Generated by Immune activation of TC cell precursors Have lytic capabilities Play critical role in recognition of altered self cells MHC I restricted (generally)  All nucleated cells in body express MHC I molecules
  • 69.
    Generation of EffectorCytotoxic T cells Cytotoxic T Requires three specific signals:  Signals for Activation 1-Primary antigen specific TCR(CD8+)-Ag-MHC I interaction  2-Co-stimulatory CD28-B7 interaction    (may not be necessary for Memory TC cell precursors ) Signals for Proliferation & Differentiation 3-Signal from IL-2 interaction with high-affinity IL-2 Receptor  Generally T cell precursors (CTL-P’s) need IL-2 produced C from TH1 cells for proliferation   Memory TC cell precursors may produce enough IL-2 to self-proliferation
  • 70.
    Cytotoxic T cellactivation
  • 71.
  • 72.
    Cytotoxic cell’s Granule CytotoxicT attach steps Mediated Homicide 1) Conjugate formation 2) Membrane attack 3) TC cell dissociation 4) Target cell obliteration (destruction)
  • 73.
  • 74.
    Cytotoxic T cell1-Granules Mediated pathway. 2- Fas-FasL pathway. Cytotoxic T cell’s Granule Mediated Homicide 1-Granules Mediated pathway 1) Conjugate formation Recognition: TCR-Ag-MHC I interaction  Embrace: LFA-1 receptor (T cell) binds to ICAM’s C on target cell membrane  2) Membrane attack 3) TC cell dissociation 4) Target cell obliteration (destruction)
  • 75.
    1) Conjugate formation 2)CytotoxicTattack Granule Mediated Homicide Membrane cell’s  Cytoplasmic rearrangement   Brings Golgi and storage granules into closer proximity to target cell Granule Secretion (exocytosis)  Perforin - 65kDa monomer    Undergoes conformational change upon contact with target cell membrane which exposes amphipathic domain, enabling insertion into membrane. Once in membrane perforins polymerize and create 5-20nm pores (w/Ca2+). Granzyme 3) TC cell dissociation 4) Target cell obliteration (destruction)
  • 76.
    Figure 14-9a: Perforinpore formation in target cell membrane
  • 77.
    Figure 14-9b: EMof perforin pores in target cell membrane
  • 78.
    Cytotoxic T cell1-Granules Mediated pathway. 2- Fas-FasL pathway. 1-Granules Mediated pathway 1) Conjugate formation 2) Membrane attack Cytoplasmic rearrangement  Granule Secretion (exocytosis)  Perforin - 65kDa monomer  Granzyme    Binds to mannose 6-phosphate receptor and internalized into target cell. The Perforin pores allow the Granzyme to exit internalized vesicles. Once inside cytoplasm of target cell, initiates reaction cascade culminating in activation of endonucleases which in turn digest DNA into oligomers of ~200bp (typical of apoptosis). 3) TC cell dissociation
  • 79.
  • 80.
    Cytotoxic T cell’sFas Ligand Mediated Homicide Fas Transmembrane protein  Member of the TNF-receptor family  Can deliver death signal when crosslinked with its natural ligand   Natural ligand is a TNF called Fas ligand (FasL) 2) FasL  Found on the membrane of TC cells  Interaction with Fas protein triggers target cell apoptosis 3) Fas-FasL interaction  elucidated by experiments with perforin
  • 81.
    Cell Death byApoptosis Caspase  Family of cysteine proteases which cleave after Asp residue  Normally present in cell as inactive proenzymes “procaspases”  >12 caspases with different specificity have been identified  Cleavage of procaspase produces an active initiator caspase, which in turn cleaves other caspases.  Both Granule and Fas mediated apoptotic signaling induces the caspase cascade (Fig14-11) by activating Procaspase-8.  Results in “systematic” disassembly of the cell
  • 82.
    Cell Organization ofC-MER Cytotoxic cells Cells with direct cytotoxic activity:  Antigen specific   + CD8+ Cytotoxic T cells (TC C cells or CTL’s) Cytotoxic T cells (T cells or CTL’s) Nonspecific Natural Killer Cells (NK cells) Natural Killer Cells (NK cells)  Macrophages  Cells that mediate the delayed-type hypersensitivity reactions (DTHR):  CD4+ TH cells TH1 cells TH1 cells T 2 cells  T H2 cells H 
  • 83.
    Tof T-cell EffectorMolecules cell functions Functions Mediate target-cell destruction by TC cells:    Fas ligand (membrane-bound) perforins (soluble) granzimes (soluble) TC cell Promote macrophage activity:    TNF-β (soluble & membrane-bound) INF-γ (soluble) GM-CSF (soluble) T H1 TH2 Play role in B-cell activation by TH2 cells:   CD40 (membrane bound) IL-4, IL-5, IL-6 (soluble)
  • 84.
    CTL deal withantigens in the cytoplasm by killing the cells that present the antigen TH1 deals mostly with antigen in macrophage vesicles by activating the macrophages. That is, antigens that have been phagocytized. Activated macrophages are more aggressive in killing phagocytized material and they release toxic compounds into the local environment. TH2 deals with antigens that were bound to a B cell’s BCRs (extracellular antigens) and internalized (into vesicles). They activate B cells for antibody secretion.
  • 85.
    For antigens tobe recognized by CTLs, they must be presented in association with MHC class I. For antigens to be recognized by TH1 or TH2, they must be presented in association with MHC class II. Therefore, CTLs are interested in proteins synthesized inside a cell whereas TH1 and TH2 are interested in proteins that were synthesized outside of a cell but were brought into the cell in vesicles
  • 86.
    The Control ofActivated CD4+ T Cells by Regulatory T cells NKT cells/ CD4+CD25+ cells CD4+CD25- cells Apoptosis peptide/APC (- ) TH1 CD4+ cells IL-12/ IFN-γ (- ) IL-10 (- ) IL-4 Resting CD4 T cells IFN-γ Activated CD4 T cells (- ) TH2 CD4+ cells Regulatory immunity CD4/CD8 interactions CD8 or CD4 suppressor effector CD8 or CD4 suppressor precursor L. Chess 2002
  • 87.
    Regulatory T cell SuppressorCell Natural Treg Regulatory cells RegulatoryTT Cell Subsets Murine Markers CD8+ CD4+, CD25+ CTLA-4+, GITR+, Foxp3+ (intracellular) Adaptive Treg CD4+, CD25 -, Foxp3Tr1 CD4+, CD45Rb lo Th3 CD4+, CD45Rb lo Invariant NKT cell Invariant TCRα (Vα14-Jα281), CD4+, CD8-, NK1.1+ Proposed Mechanisms of Inhibition Recogn ition of Qa-1:peptide on activated CD4+ T cells → induction of cytotoxicity Cell-contact dependen t but not antigen-specific; Ligation of B7 on effector cells; IL-2 sequestration; CTLA-4 interaction with IDO → tolerogenic DCs; IL-10 & TGF-beta production Cell-contact dependen t but not antigen-specific inhibition Cell-contact independen t; IL-10 & IL-4 secretion Cell-contact independen t; TGF-beta secretion CD1d:glycolipid complex recogn ition; IL-10 secretion
  • 88.
    Natural Killer (NK)Cells Functions 1-showed significant lysis of tumor cells. Compose 5-10% of recirculating lymphocyte population Involved in immune defense against virus and tumors 2-Play important role in immune regulation:  Influence both adaptive and innate immunity via cytokine production/excretion:  INFγ:  Affects phagocytic and microbial activities of macrophages  Influences T 1 cells vs T 2 cells commitment of development H H 3-First line of defense in viral infections  Number of NK cells peaks ~3 days after infection
  • 89.
    Comparison between NKand T Cells Similarities   Common early progenitor (Lymphoid progenitor) Express some common membrane markers:    CD2 75 kDa β subunit of the IL-2 receptor *CD16 Receptor for Fc region of IgG Differences   NK cells do not develop exclusively in the thymus Do not undergo rearrangement of receptor genes
  • 90.
    Comparison of NKand T-cell Assassination Mechanism Similar to processes employed by CTL’s    Express FasL on membrane surface Contain Granules of perforin and granzimes Target cell degradation occurs via perforins and granzymes Different from CTL’s cytotoxicity     NK always cytotoxic, do not need to be activated to produce granules Do not express Ag specific T-cell receptors or CD3 Recognition of target cells is NOT MHC restricted NK immune response generates no immunological memory  No greater immune response upon secondary infection
  • 91.
    Natural Killer (NK)Cells Express inhibition and activation receptors on cells surface  Many inhibition and many activation receptors create an opposingsignal model.  The balance between the opposing signals is believed to enable NK to differential between healthy and infected cells (Fig 14-14) Additional NK activator signals can be delivered by soluble factors  TNF-α, IL-12, and IL-15 NK cells may target cells that produce aberrant MHC expression  Many virus-infected and tumor cells have reduced MHC expression
  • 92.
    NK Cells Inhibitor-ReceptorSuperfamily C-type-lectin-inhibitory receptor (CLIR)  In humans: CD94/NKG2 - disulfide bonded heterodimer of two glycoproteins  Recognizes HLA-E on potential target cells   HLA-E serves as indicator of overall level of MHC I biosynthesis Thus CD94/NKG2 are not specific for specific HLA allele Killer-cell-inhibitory receptors (KIR)  A group of Ig-superfamily-inhibitory receptors (ISIR)   more than 50 family members have been found Specific for one or more of polymorphic HLA products Inhibitory receptors have veto power over activation receptors   Thus, cells expressing normal levels of MHC I receptors tend to escape all forms of NK assassination. Thus cells that lack normal MHC I expression = lack of normal self expression DIE!!!
  • 93.
    Fig. 14-14: Opposing-signalsmodel of cytotoxic activity
  • 94.
    What is NKTCells? Immunology Today November 2000 Vol21 No.11 573
  • 95.
    Characteristics  Express both Tcell receptors and NK1.1 receptors — hence its name.  Respond to glycolipid antigens presented by CD1d  CD1 restricted rather than MHC restricted  CD4+ or Double negative, in mice  Secrete large amounts of either IFN-γ, IL-4, TNF  Lack immunological memory
  • 96.
    1.Control of infection CurrentBiology Vol 15 No 11,2005
  • 97.
    2.Bridging innate and acquiredimmunity VOLUME 4 NUMBER 12 DECEMBER 2003 NATURE IMMUNOLOGY
  • 98.
    Models of Memory LymphocyteDevelopment Ag + Co-stimulation Effector Cell CLASSIC THEORY Activated cell in Environment X Ag Naïve cell Activated cell in Environment Y Memory Cell Ag Effector Cell Precursor KLINMAN LINEAGE HYPOTHESIS Effector Cell Ag Ag Memory Cell Precursor Memory Cell Effector Cell
  • 99.
    Ag + Costimulation Ag Apoptotic Death 95to 99% 1 to 5% Naïve Cell Activated cell Effector Cell LINEAR DIFFERENTIATION MODEL Ag + Costimulation Memory Cell Activated cell Activated/Effector Cell Ag Effector Cell Ag Naïve Cell Memory Cell Memory Cell Memory Cell DIMINISHING POTENTIAL MODEL