NK cells in Viral immunity
By
Manmohan Mishra
Msc Virology
9/10/2013
HISTORY
OVERVIEW OF NK CELL
NATURAL KILLER CELL
If there is no MHC-1 on intestinal
Cells, what will happen to then ?
ACTIVATION - ...
Development of NK cell
INTRODUCTION
• NK cells (group Innate lymphoid cells) – large(15µm), granular, bone
marrow-derived lymphocytes that displa...
NK CELL CD SURFACE MARKERS AND FUNCTIONS
CD NUMBER FUNCTION
CD2 ADHESION MOLECULE & BINDS CD58
ACTIVATES NK CELLS
CD11b PH...
• NK cells - 5%–10% of total lymphocytes in human Peripheral
Blood
• NK cells differ from NK1-T phenotypically, by origin ...
NK1-TCELL
CHARACTERISTIC
OF BOTH NK & T
CELL
LIKE TCELLS THEY HAVE
TCR INTERACT WITH MHC
LIKE MOLECULE CD1
RATHER THAN MHC...
Role of NK cell in Innate & Adaptive
immunity
• Nk cells - effectors of innate immunity
• NK cell - role in adaptive immun...
ROLE IN INNATE IMMUNITY
• NK cell–dendritic cell crosstalk
-NK cells can kill iDCs, NK cells and DCs reciprocally activate...
NK cell function in adaptive response
 Ability to generate memory cells following a primary infection
 Consequent rapid ...
NK cell receptors
• NK cell receptors - differentiated based on function.
• 2 different categories of receptors
TWO RECEPT...
ACTIVATION
RECEPTORS
Ig SF
CD16 (FcγRIII),
CD28,
KIR2S, KIR3S,
NCR (NKp30, 44, 46),
ILT-1 (Ig-like
transcript 1)
Cyto R
CD...
INHIBITORY RECEPTORS
IgSF
CD85
H
ITIM
HLA-
A,B,G
KIR2DL/3DL
H
ITIM
HLA-1
C-LECTIN
CD94/NKG2A
H,M
ITIM
HLA-E
CD161
M
ITIM
N...
Missing 'self' hypothesis
• Opposing-signals model - balance betn
activating signals and
inhibitory signals - enable NK cells to distinguish healthy...
NKG2D MECHANISM
CMV VS NKG2D
CMV VS NK CELL
Acquisition of NK cell function
Function
CYTOTOXIC MECHANISMS (THE ‘WEAPONS’)
• NK cells are cytotoxic
small granules in their cytoplasm contain proteins ...
PERFORIN
PORE FORMING
PROTEIN
ENCODED BY
PRF1 GENE
CYTOLYTIC
PROTEIN FOUND IN
GRANULES CTLs &
NK CELLS
UPON DEGRANULATION
...
GRANULE EXOCYTOSIS
GRANZYME
B
Protease located in
cytoplasmic granules
of killer cells
Cleaves after
aspartate residues
that have the
sequenc...
GRANZYME -A APOPTOSIS PATHWAY
NK CELL
Antibody-dependent cell mediated cytotoxicity( ADCC)
Cytokine-induced NK and CTL
activation
• Cytokines play a crucial role in NK cell activation
• Cytokines- stress molecules...
Nk cells respond to IL-12 produced by macrophages & secrete
IFN- γ, which activates the macrophages to kill phagocytosed
m...
NK CELL CYTOKINES
Interferon gamma (IFN-γ):
- activation, growth and differentiation of T, B, NK cells and macrophages
-pr...
Granulocyte/macrophage colony stimulating factor
(GM-CSF):
-survival and growth factor of HSCs
-differentiation and activa...
• They serve to contain viral infections while the adaptive immune
response is generating antigen-specific cytotoxic T cel...
ANTIVIRAL FUNCTIONS
ULBP
NKG2D
Nk cells in viral immunity
Nk cells in viral immunity
Nk cells in viral immunity
Nk cells in viral immunity
Nk cells in viral immunity
Nk cells in viral immunity
Nk cells in viral immunity
Nk cells in viral immunity
Nk cells in viral immunity
Nk cells in viral immunity
Nk cells in viral immunity
Nk cells in viral immunity
Nk cells in viral immunity
Nk cells in viral immunity
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Nk cells in viral immunity

  1. 1. NK cells in Viral immunity By Manmohan Mishra Msc Virology 9/10/2013
  2. 2. HISTORY
  3. 3. OVERVIEW OF NK CELL NATURAL KILLER CELL If there is no MHC-1 on intestinal Cells, what will happen to then ? ACTIVATION - IL-12, IFN-ᵞ MATURATION - DNN THYMUS, INTRACELLULAR PATHOGEN MATURE IN BONE MARROW ANTIGEN - DO NOT NEED EXPOSURE TO ANTIGEN SP. ANTIBODY - NO MEMORY ABILITY MARKERS- NO CD4, CD8, CD3 YES- CD16,56 Intracellular Extracellular Pathogen Pathogen TH0 IL-12 IL-4 IFN-ᵞ × TH1 TH2 × IL-2 IL-4,5,6,10,13 IFN-ᵞ TNF TGF-ß IL-12 ,IFN- ᵞ
  4. 4. Development of NK cell
  5. 5. INTRODUCTION • NK cells (group Innate lymphoid cells) – large(15µm), granular, bone marrow-derived lymphocytes that display cytotoxic activity against a wide range of tumor cells in the absence of any previous immunization with the tumor. • Named “NK cells” - initial notion - do not require activation to kill cells that are missing “self” markers of MHC class 1 • NK cells donot express TCR or B cell surface immunoglobulins. NK cell
  6. 6. NK CELL CD SURFACE MARKERS AND FUNCTIONS CD NUMBER FUNCTION CD2 ADHESION MOLECULE & BINDS CD58 ACTIVATES NK CELLS CD11b PHAGOCYTOSIS OF iC3b COATED PARTICLES CD11c SIMIAR FUNCTION TO CD11b CD16 IMMUNE COMPLEX INDUCED CELLULAR ACTIVATION, ADCC CD56 HOMOTYPIC ADHESION
  7. 7. • NK cells - 5%–10% of total lymphocytes in human Peripheral Blood • NK cells differ from NK1-T phenotypically, by origin and by respective effector functions • Sometimes NK1-T cell activity promotes NK cell activity by secreting IFNγ
  8. 8. NK1-TCELL CHARACTERISTIC OF BOTH NK & T CELL LIKE TCELLS THEY HAVE TCR INTERACT WITH MHC LIKE MOLECULE CD1 RATHER THAN MHC 1 OR 2 LIKE NK THEY HAVE CD16 (VARIABLE LEVEL) & OTHER RECEPTORS & THEY KILL INFECTED CELLS A popln of NK1-T cells - rapidly secrete large amounts - cytokines - support antibody prodn by B cells, inflammation and the development and expansion of CTLs. TLR signaling- result in the recruitment and activation of macrophages, NK cells, and dendritic cells, key agents in the presentation of antigen to T cells
  9. 9. Role of NK cell in Innate & Adaptive immunity • Nk cells - effectors of innate immunity • NK cell - role in adaptive immune response • The ability for NK cells in both the innate and adaptive immune response - important in research utilizing NK cell activity and potential cancer therapies
  10. 10. ROLE IN INNATE IMMUNITY • NK cell–dendritic cell crosstalk -NK cells can kill iDCs, NK cells and DCs reciprocally activate one another during an immune response
  11. 11. NK cell function in adaptive response  Ability to generate memory cells following a primary infection  Consequent rapid immune activation  Response to succeeding infections by the same antigen (Fundamental to the role T and B cells play in the adaptive immune response)  Despite prior belief - NK cells play no role in the adaptive immune responses, been found to undergo expansion, contraction, memory maintenance and recall
  12. 12. NK cell receptors • NK cell receptors - differentiated based on function. • 2 different categories of receptors TWO RECEPTOR MODEL Inhibitory receptors – delivers inhibition signals to NK cells Activation receptors- delivers activation signals
  13. 13. ACTIVATION RECEPTORS Ig SF CD16 (FcγRIII), CD28, KIR2S, KIR3S, NCR (NKp30, 44, 46), ILT-1 (Ig-like transcript 1) Cyto R CD25 (IL-2Rα) CD122 (IL-2Rβ) IFN-α/βR TNFRSF CD27 C-lectin CD69 CD94/NKG2C, E CD161 NKG2D Ly49D, H, P CD16 SPECIES- H, M MOTIF/ADAPTOR- ITAM/FcᵞR LIGAND- IMMUNE COMLEX-ADCC CD28- SPECIES- H,M MOTIF/ADAPTOR- YXXM/P13K LIGAND- CD 80,86 CD226 SPECIES- H LIGAND- CD112,CD155 KIR2S/KIR3S SPECIES- H MOTIF/ADAPTOR- ITAM/DAP12 LIGAND – HLA 1 CD25(IL-2Rß)- H LIGAND- IL-2 CD122(IL- 2Rß) H,M JAK-STAT IL-2,15 IFN-αßr H,M JAK –STAT LIGAND- TYPE1 IFN CD27 H,M TRAF CD70 CD69 H,M CD94/NK G2C- H,M ITAM/DA P12 HLA,E LY49 M ITAM/DA P12 H-2 NCR(NKP30,44,4 6) H,M(NKp46) ITAM/DAP12 VIRAL HAEMAGGLUT ININS -
  14. 14. INHIBITORY RECEPTORS IgSF CD85 H ITIM HLA- A,B,G KIR2DL/3DL H ITIM HLA-1 C-LECTIN CD94/NKG2A H,M ITIM HLA-E CD161 M ITIM NKR- P1D LY49 M ITIM H-2 KLRG1 M ITIM SLAM CD244- H,M TXYXXV-1 CD-48 CYTO-R TGF-ßr H,M Smad2 TGF-ß FAMILY IL-10R JAK- STAT IL-10
  15. 15. Missing 'self' hypothesis
  16. 16. • Opposing-signals model - balance betn activating signals and inhibitory signals - enable NK cells to distinguish healthy cells from infected or cancerous ones. IRs- in cytoplasmic domain structural motif ITIMs As IR bind MHC-1 ITIMs phosphorylated on tyrosine residues – phosphorylated ITIMs bind and promote the action of cytoplasmic protein tyrosine phosphatases. These phosphatases remove the phosphate group of from tyrosine residues of various signaling molecules thus block the activation of NK Cells Through Activation Receptors
  17. 17. NKG2D MECHANISM
  18. 18. CMV VS NKG2D
  19. 19. CMV VS NK CELL
  20. 20. Acquisition of NK cell function
  21. 21. Function CYTOTOXIC MECHANISMS (THE ‘WEAPONS’) • NK cells are cytotoxic small granules in their cytoplasm contain proteins - Perforin and proteases known as Granzymes  Upon release - close proximity to a cell , perforin forms pores in the cell membrane - target cell - an aqueous channel through which the granzymes , associated molecules enter - inducing either apoptosis or osmotic cell lysis  Lysing a virus-infected cell- potentially only release the virions, whereas Apoptosis leads to destruction of the virus inside.  α-defensins, an antimicrobial is also secreted by NK cells, directly kills bacteria by disrupting their cell walls analogous to neutrophils
  22. 22. PERFORIN PORE FORMING PROTEIN ENCODED BY PRF1 GENE CYTOLYTIC PROTEIN FOUND IN GRANULES CTLs & NK CELLS UPON DEGRANULATION INSERTS ITSELF INTO TARGET CELL PLASMA MEMBRANE, FORMS PORE OR ENDOSOME ALLOWINGRANZYMES TO ENTER TARGET CELL CYTOPLASM THE LYTIC MEMBRANE- INSERTING PART OF PERFORIN IS MACPF DOMAIN Granulysin - (humans) function similarly to perforin
  23. 23. GRANULE EXOCYTOSIS
  24. 24. GRANZYME B Protease located in cytoplasmic granules of killer cells Cleaves after aspartate residues that have the sequence: Ile/Val- Gly/Met/Glu-X-Asp- X-Gly Caspase 3 and 8 are direct substrates for granzyme B Caspases are cysteine proteinases involved in apoptosis Other granzymes in granules (granzyme A, K, M)
  25. 25. GRANZYME -A APOPTOSIS PATHWAY NK CELL
  26. 26. Antibody-dependent cell mediated cytotoxicity( ADCC)
  27. 27. Cytokine-induced NK and CTL activation • Cytokines play a crucial role in NK cell activation • Cytokines- stress molecules released by cells upon viral infection, they serve to signal to the NK cell the presence of viral pathogens. • Cytokines involved in NK activation include IL-12, IL-15, IL-18, IL-2, and CCL5. • NK cells - activated in response to interferons or macrophage- derived cytokines.
  28. 28. Nk cells respond to IL-12 produced by macrophages & secrete IFN- γ, which activates the macrophages to kill phagocytosed microbes
  29. 29. NK CELL CYTOKINES Interferon gamma (IFN-γ): - activation, growth and differentiation of T, B, NK cells and macrophages -promotes Th1 differentiation -enhances MHC expression on APC -some direct anti-viral activity Tumour necrosis factor alpha (TNF-α): -paracrine and endocrine mediator of inflammation -regulates growth and differentation of a wide variety of cells -selectively cytotoxic for many transformed cells
  30. 30. Granulocyte/macrophage colony stimulating factor (GM-CSF): -survival and growth factor of HSCs -differentiation and activating factor for granulocytic and monocytic cells -growth factor for endothelial cells, erythroid cells, megakaryocytes and T cells
  31. 31. • They serve to contain viral infections while the adaptive immune response is generating antigen-specific cytotoxic T cells that can clear the infection. • NK cells work to control viral infections by secreting IFN γ and TNF α. • IFN γ activates macrophages for phagocytosis and lysis, and TNFα acts to promote direct NK tumor cell killing. • Patients deficient in NK cells prove to be highly susceptible to early phases of herpes virus infection.
  32. 32. ANTIVIRAL FUNCTIONS
  33. 33. ULBP NKG2D
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