Cell Mediated Immunity PDF

Outlines Cell Mediated  Describe the development of T lymphocyte Immunity  Describe the mechanisms of naïve CD4+ and CD8+ T cells activation before differentiating into effector...

Outlines Cell Mediated  Describe the development of T lymphocyte Immunity  Describe the mechanisms of naïve CD4+ and CD8+ T cells activation before differentiating into effector and memory T cells Dr Hanan Hamimi Binti Wahid  Describe the functions of effector CD4+ T cells and CD8+ T cells [email protected]  Describe the properties and functions of memory T cells  Describe the properties and functions of lymphocytes 1 that are considered as cells of innate immunity 2 Hematopoeisis Adaptive Immunity Cell mediated immunity CD4+ CD8+ 3 4  6 Cell mediated immunity Cell mediated immunity Thymus 5 6 Cell mediated immunity Cell mediated immunity Double negative thymocytes/ pro-T stage (cortex) Thymocytes haven't expressed TCR, CD3, CD4 OR CD8 Cortex Medulla Thymocytes express Rag-1 and Rag-2 genes 7 8  Cell mediated immunity Cell mediated immunity Double negative thymocytes/ pre-T stage (cortex) Double positive thymocytes (cortex) Expression of both CD4 and CD8 Productive rearrangement of the TCR β chain genes happens, leading to TCR β chain expression Rearrangement of the TCR α chain genes 9 happens in CD4+ and CD8+ thymocytes 10 Cell mediated immunity Cell mediated immunity Double positive thymocytes (cortex)- Double positive thymocytes (cortex) Positive selection A process in which thymocytes with TCR that binds to self peptide on self MHC with low avidity are stimulated to survive Self peptides- widely expressed protein antigens and from some proteins restricted to particular tissues Expression of TCR αβ heterodimers that can either recognise OR do not recognise peptide antigens displayed on self MHC 11 12  Cell mediated immunity Cell mediated immunity Double positive thymocytes (cortex)- Double positive thymocytes (cortex)- Positive selection Positive selection Why we don’t have presentation of foreign antigens Self peptides-displayed by thymic cortico here?? epithelial cells on self MHC I or II Thymocytes with TCR that can't recognise self peptide on self MHC I or II- die by apoptosis 13 14 Cell mediated immunity Cell mediated immunity Double positive thymocytes (cortex)- Double positive thymocytes (cortex)- Positive selection Positive selection Why we don’t have presentation of foreign antigens Why do you think positive selection is important? here?? 15 16  Cell mediated immunity Cell mediated immunity Double positive thymocytes (cortex)- Double positive thymocytes (cortex)- Positive selection Positive selection Why do you think positive selection is important? What about the T cells with TCR that binds to self peptide on self MHC with high avidity? 17 18 Cell mediated immunity Cell mediated immunity Double positive thymocytes (cortex)- Negative selection/ central tolerance Transition from double positive thymocytes to single positive thymocytes The process in which thymocytes with TCR that binds to self peptide on self MHC with high avidity undergo apoptosis or differentiate into regulatory T cells Self peptides- are displayed by thymic cortico epithelial cells on self MHC I or II 19 20  Cell mediated immunity Cell mediated immunity Transition from double positive thymocytes to Single positive thymocytes (in medulla) single positive thymocytes Thymocytes with MHC I-restricted TCRs become CD8+CD4- cells Thymocytes with MHC II-restricted TCRs become CD8-CD4+ cells 21 22 Cell mediated immunity Cell mediated immunity Single positive thymocytes (in medulla) Negative selection/ central tolerance Single positive thymocytes (in medulla) Self peptides- displayed by thymic medullary epithelial cells, dendritic cells and macrophages on self MHC I or II From medulla, CD4+ and CD8+ thymocytes exit the thymus through the circulation to populate Thymic medullary epithelial cells- express a secondary lymphoid organs (lymph nodes, spleen nuclear protein (AIRE ) and MALTs) AIRE- induces the low-level expression of a number of tissue-specific genes (self antigens) peptides available for presentation to developing T cells 23 24 Cell mediated immunity Cell mediated immunity Differentiation of naive T cells (CD4+ and CD8+ T Differentiation of naive T cells (CD4+ and CD8+ T cells) to effector T cells cells) to effector T cells Signals by molecules on APCs (costimulators) Mature dendritic cells (and other APCs) express B7-1 (CD80) or B7-2 (CD86) which will bind CD28 on the surface of activated T 25 cells 26 Cell mediated immunity Cell mediated immunity Differentiation of naive T cells (CD4+ and CD8+ T Differentiation of naive T cells (CD4+ and CD8+ T cells) to effector T cells cells) to effector T cells Proliferation of antigen- IL2 specific lymphocytes  Acts on the same T cells that produce it Clonal expansion or on adjacent T cells (increase in the number of antigen spec clones)  Stimulates the survival, and differentiation of proliferation and naive lymphocytes into differentiation of effector and memory activated T cells 27 lymphocytes 28  Cell mediated immunity Cell mediated immunity Effector CD4+ T Effector CD4+ T Naïve CD4+ T cells cells cells (Secondary (Site of (Thymus) lymphoid infection/ T helper 1 Cytotoxic T Effector CD4+ T cells Effector CD8+ T cells organs) inflammation) (Th1) cells lymphocytes (CTLs) T helper 2 Effector CD8+ T Effector CD8+ T (Th2) cells Naïve CD8+ T cells cells cells (Secondary (Site of (Thymus) lymphoid infection/ T helper 17 (Th17) cells organs) inflammation) 29 30 Cell mediated immunity Cell mediated immunity Effector functions of Th1 cells- Effector functions of Th1 cells- Cytokines (IFNγ/ type II interferon) Th1-mediated macrophage activation Activates macrophages to kill phagocytosed CD40L interaction with microbes CD40 on surface of macrophages Promotes differentiation of CD4+ T cells to Th1 subsets and inhibits the differentiation of Th2 and IFN gamma secreted Th17 cells by Th1 binds to IFN gamma receptor on Stimulates the expression of several proteins that macrophages to contribute to enhance antigen presentation (MHC) activate and T cell activation (co stimulators) macrophages 31 32 Cell mediated immunity Cell mediated immunity Effector functions of Th1 cells- Effector functions of Th1 cells- Responses of activated Responses of activated macrophages: macrophages Produce reactive Secrete cytokines, oxygen species, nitric chemokines and lipid oxide and increased mediators - recruit more lysosomal enzymes leukocytes 33 34 Cell mediated immunity Cell mediated immunity Effector functions of Th1 cells- Effector functions of Th2 cells- Cytokines (IL4, IL5, IL13) IL4 Responses of activated Stimulates B cell Ig heavy chain class switching to macrophages IgE isotype Increase expression of Stimulates recruitment of eosinophils MHC II molecules to become more efficient Stimulates peristalsis in gastrointestinal tract APCs to amplify T cell response 35 36  Cell mediated immunity Cell mediated immunity Effector functions of Th2 cells- Effector functions of Th2 cells- Cytokines (IL4, IL5, IL13) Cytokines (IL4, IL5, IL13) IL5 IL13 Activates mature eosinophils and stimulates the growth and differentiation of eosinophils to kill Stimulates B cell Ig heavy chain class switching to helminths IgE isotype Stimulates recruitment of eosinophils Stimulates peristalsis in gastrointestinal tract Increases mucus secretion from airway and gut 37 epithelial cells 38 Cell mediated immunity Cell mediated immunity Effector functions of Th2 cells- Effector functions of Th2 cells- Response to helminth parasites Response to helminth parasites Stimulate the production Stimulate the production of IgE by B cells of IgE by B cells B cells act as APCs to B cells act as APCs to internalize the antigens internalize the peptides from helminths, present from helminths, present the peptides to Th2 them to Th2 cells, which cells, which will be will be activated to activated to produce produce IL4 (stimulate B IL4 (stimulate B cells to cells to produce IgE) produce IgE) 39 40 Cell mediated immunity Cell mediated immunity Effector functions of Th2 cells- Effector functions of Th2 cells- Response to helminth parasites Response to helminth parasites Recruit and activate Stimulate the production eosinophils of IgE by B cells IgE will coat the Mast cells express helminths and high affinity Fc promote the binding receptor for IgE. to eosinophils Upon binding to IgE IL5 promotes the coated with activation eosinophils, helminths, mast cells to release granule will degranulate to contents to destroy cause expulsion of 41 helminths 42 helminths Cell mediated immunity Cell mediated immunity Effector functions of Th2 cells- Effector functions of Th17 cells- Response to helminth parasites Cytokines (IL17, IL22) Barrier immunity (IL17 To promote expulsion of microbes from mucosal IL17 organs by: Induces neutrophil-rich inflammatory reactions- by stimulating the production of cytokines and increasing the mucus chemokines that recruit neutrophils and monocytes secretion from airway to site of T cell activation and gut epithelial cells Stimulates production of antimicrobial substances stimulating peristalsis like defensins, from numerous cell types in gastrointestinal 43 44 tract  Cell mediated immunity Cell mediated immunity Effector functions of Th17 cells- Effector functions of Th17 cells- Cytokines (IL17, IL22) Response to extracellular microbes (IL17 IL22 Produced in epithelial tissues (skin and GI tract) to maintain epithelial integrity by:  promoting barrier function  stimulating repair functions  inducing production of antimicrobial peptides Stimulates epithelial production of chemokines to contribute to inflammation 45 46 Cell mediated immunity Cell mediated immunity Effector functions of CTL Effector functions of CTL Cytokines (IFN- γ, IL17) Response to microbes that:  infect and replicate in the cytoplasma of various cell types IFN-γ  escape the phagosome and reside in the Activate macrophages to kill phagocytosed cytoplasma of phagocytes (Mycobacterium microbes tuberculosis) IL17 Response to tumor cells (TUMOR IMMUNOLOGY Induce inflammatory reactions- chronic LECTURE) inflammatory diseases of the skin (psoriasis) Acute rejection of organ allografts (TRANSPLANTATION IMMUNOLGY LECTURE) 47 48 Cell mediated immunity Cell mediated immunity Effector functions of CTL Effector functions of CTL Mechanisms of CTL- mediated lysis of target cells Mechanisms of CTL- mediated lysis of target cells Recognition of antigen Target cells express: Granule-dependent mediated killing Peptide-MHC complex serves a Once activated, CTL ligand for TCR and delivers cytotoxic binds CD8 (co- protein in granules receptor) of CTLs (granzymes and perforins) to target cells ICAM-1 interact with to trigger apoptosis of LFA-1 of CTLs target cells (adhesion molecules) 49 50 Cell mediated immunity Cell mediated immunity Effector functions of CTL Mechanisms of CTL- mediated lysis of target cells Memory T cells  Live long (years) without continuous antigen stimulation - Granule-independent because express high level of anti-apoptotic protein Bcl-2 mediated killing Once activated, CTLs  Mount rapid response to subsequent introduction of antigen express FAS ligand (FasL) that binds to death  The number is higher than naïve T cells specific for the receptor Fas on target same antigen cells, to activate caspases and apoptosis of target cells 51 52  Cell mediated immunity Cell mediated immunity Memory T cells  Less dependent on co-stimulation than the naïve T cells T helper 1 Cytotoxic T Effector CD4+ T cells Effector CD8+ T cells  Migrate to peripheral tissues (any tissues) (Th1) cells lymphocytes T helper 2 (CTLs) (Th2) cells T helper 17 (Th17) cells T regulatory cells (Treg)?? 53 54 Cell mediated immunity Cell mediated immunity TGFβ – IL2 - survival and Natural development of Peripheral Natural functional Peripheral Treg cells Treg cells Treg cells Treg cells competence of Treg cells Treg cells 55 56  Cell mediated immunity Cell mediated immunity Effector functions of Treg cells- Effector functions of Treg cells- Immunosuppressive Cytokines (TGFβ and IL10) Immunosuppressive Cytokines (TGFβ and IL10) TGFβ inhibits the proliferation and effector functions of T IL10 cells inhibits the production of IL-12 by activated Inhibits the activation of macrophages. dendritic cells and macrophages. stimulates production of IgA antibodies by inhibits the expression of costimulators and class II inducing B cells to switch to IgA isotype MHC molecules on dendritic cells and macrophages promotes tissue repair following local immune and inflammatory reactions. 57 58 Innate Immunity Innate Immunity NKT cells  Lymphocytes that are more akin to cells of innate immunity rather than cells of adaptive immunity:  Double positive αβ T cells that express TCR that can recognize CD1 molecules expressed by neighbouring Natural Killer T cells (NKT cells) double positive thymocytes are induced to γδ T cells differentiate into NKT cells Innate lymphoid cells (ILCs) Mucosa-Associated Invariant T (MAIT) cells??  Have surface markers expressed by NK cells (CD56) B1 cells 59 60  Innate Immunity Innate Immunity NKT cells NKT cells  Express αβ TCR:  Protective innate immune response against mycobacteria (lipid rich cell walls) with limited diversity- invariant TCR  Can produce cytokines (IL4 and IFNγ) rapidly after that are CD1 restricted- TCR can recognize lipid and activation, which may help marginal zone B cells to glycolipid antigens that are bound to CD1 molecules produce antibodies against lipid antigens (class I MHC-like molecules)  Secrete cytokines that regulate adaptive immune  Not MHC restricted and can’t recognize peptides response (αβ T cells and B cells) displayed by antigen-presenting cells 61 62 Innate Immunity Innate Immunity γδ T cells  Lymphocytes that are more akin to cells of innate  Rearrangement of the TCR β, γ and δ chain genes immunity rather than cells of adaptive immunity: can happen at the same time Natural Killer T cells (NKT cells)  Develop when a thymocyte succeeds in rearranging γδ T cells its TCR γ and δ chain genes, before it makes a productive TCR β chain gene rearrangement Innate lymphoid cells (ILCs) Mucosa-Associated Invariant T (MAIT) cells?? B1 cells 63 64  Innate Immunity Innate Immunity γδ T cells γδ T cells  Present in blood, lymphoid tissues, skin, intestinal  Not MHC restricted and do not require antigen epithelium and pulmonary epithelium processing and presentation  Less diversity in the γδ T cell receptors  Receptor binds to the phospholipid (M.tuberculosis) same way as when B cell receptors bind to epitopes  Express CD3, but not CD4 or CD8  May initiate immune responses to microbes at epithelia by secreting cytokines and killing infected  Recognise protein and lipid antigens cells 65 66 Innate Immunity Innate Immunity ILCs cells  Lymphocytes that are more akin to cells of innate  Derived from lymphoid progenitor cells in bone immunity rather than cells of adaptive immunity: marrow Natural Killer T cells (NKT cells)  Resident in epithelial barrier tissues, to possibly γδ T cells provide host defense against pathogens before Innate lymphoid cells (ILCs) effector T cells can differentiate and proliferate Mucosa-Associated Invariant T (MAIT) cells?? B1 cells  Produced cytokines similar to T cells, they lack of TCRs 67 68 Innate Immunity ILCs cells References  Cellular and Molecular Immunology (Ninth edition)- Abul K Abbas, Andrew H. Litchman, Shiv Pillai (Elsevier)  Kuby Immunology (Sixth edition)- Thomas J. Kindt, Richard A. Golsby, Barbara A. Osborne (Freeman) 69 70