Adaptive immunity

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

heptamer

J

Spacers and nonamers not shown

D
D

heptamer

J

CDR3

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)

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

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


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

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

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

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 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

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 cell’s Granule
Cytotoxic T attach steps Mediated Homicide
1) Conjugate formation
2) Membrane attack
3) TC cell dissociation
4) Target cell obliteration (destruction)

Cytotoxic T cell 1-Granules Mediated pathway.
2- Fas-FasL pathway.
Cytotoxic T cell’s Granule Mediated Homicide
1-Granules Mediated pathway
Recognition: TCR-Ag-MHC I interaction
 Embrace: LFA-1 receptor (T cell) binds to ICAM’s
C
on target cell membrane


2) Membrane attack

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


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
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).


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

Adaptive immunity

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Adaptive immunity