Nk cells in viral immunity
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NK cells play important roles in both innate and adaptive immunity. As part of the innate immune system, NK cells help control viral infections through cytotoxic killing of infected cells and by secreting cytokines like IFNγ and TNFα that activate macrophages. NK cells express activating and inhibitory receptors that allow them to distinguish healthy "self" cells from infected or abnormal cells. The balance of signals through these receptors determines whether an NK cell mounts an immune response. NK cells also contribute to adaptive immunity by developing a form of immunological memory, responding more rapidly upon secondary exposure to pathogens.
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Nk cells in viral immunity
- 2. NK cells in Viral immunity By Manmohan Mishra Msc Virology 9/10/2013
- 3. HISTORY
- 4. 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
- 5. Development of NK cell
- 8. 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
- 9. 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
- 10. • 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
- 11. 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
- 12. 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
- 13. 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
- 15. 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
- 16. 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
- 17. 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 -
- 20. • 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
- 21. NKG2D MECHANISM
- 22. CMV VS NKG2D
- 23. CMV VS NK CELL
- 24. Acquisition of NK cell function
- 26. 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
- 27. 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
- 29. 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)
- 31. GRANZYME -A APOPTOSIS PATHWAY NK CELL
- 32. Antibody-dependent cell mediated cytotoxicity( ADCC)
- 33. 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.
- 34. Nk cells respond to IL-12 produced by macrophages & secrete IFN- γ, which activates the macrophages to kill phagocytosed microbes
- 35. 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
- 36. 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
- 37. • 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.
- 40. ULBP NKG2D