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Cell-cell interactions in immune responses

Cell-cell interactions in immune responses. Jennifer Nyland, PhD Office: Bldg#1, Room B10 Phone: 733-1586 Email: jnyland@uscmed.sc.edu. Teaching objectives. To discuss the central role of Th cells in immune responses

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Cell-cell interactions in immune responses

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  1. Cell-cell interactions inimmune responses Jennifer Nyland, PhD Office: Bldg#1, Room B10 Phone: 733-1586 Email: jnyland@uscmed.sc.edu

  2. Teaching objectives • To discuss the central role of Th cells in immune responses • To describe the cell-cell interactions which occur in 1) Ab responses to T-dependent Ag, 2) generation of CTL, 3) activation of macrophages and NK cells • To discuss responses to T-independent Ag • To discuss mechanisms of killing by CTL and macrophages

  3. Cell-cell interactions • Immune cells interact in two ways • Direct contact between cells • Cytokine signaling acting in autocrine or paracrine fashion

  4. TCR Central role of Th cells Ag Th cell T0 cell B cell K cell Macrophage • Type of immune response: • B activation or CTL generation • Proliferation of effector cells • Enhance functional activities of other cells Eosinophil Cytokines MHC NK cell APC Cytokines

  5. Subpopulations of Th cells preTh Th0 Th1 Th2 Th17 IFN-γ, IL-2 IL-12 • Subpopulations based on cytokine profiles • Th0, Th1, Th2, Th17 • Differentiation determined by cytokines IL-4 IL-2 IL-4, IL-5, IL-6, IL-10 IFN-γ, IL-2, IL-4, IL-5, IL-10 IL-1, 6, 23 IL-17

  6. Subpopulations of Th cells Th1 Th2 B cell • Th1 cytokines • Activate macrophages • Enhance generation of CTL • inflammation • Th2 cytokines • Activate B cells • Activate granulocytes • Ab-mediated immune response Macrophage IFN-γ inhibits prolif IL-10 inhib productn IL-10 IL-5 IL-6 IL-4 Eosinophil IFN-γ IL-2 Activates Activates Mast cell Ab production

  7. Subpopulations of Th cells Th1 Th2 B cell • Regulation • Ag • IFN-γ inhibits proliferation of Th2 cells & differentiation of Th17 • IL-10 inhibits production of IFN-γ • IL-4 inhibits production of Th1 & differentiation of Th17 Macrophage IFN-γ inhibits prolif IL-10 inhib productn IL-10 IL-5 IL-6 IL-4 Eosinophil IFN-γ IL-2 Activates Activates Mast cell Ab production

  8. Cell-cell interactions inAb responses Responses to exogenous Ag T-dependent Ag

  9. Hapten-carrier effect • Studies on Ab response to hapten-carrier conjugates show • Both Ts and Bs required for Ab production • Th cells recognize carrier determinants • Bs recognize haptenic determinants • Interactions are class II self MHC restricted • Bs function in Ag recognition and presentation

  10. Mechanism of hapten-carrier effect Ag Ag CD40 BCR BCR MHC MHC B cell B cell TCR Thcell 1. • Hapten recognized by BCR = signal 1 • Hapten-carrier endocytosed and processed • Carrier determinants presented in context of MHC class II to Th2 cells Hapten binds BCR Endocytosed Ag presented CD28 CD80/86 2. CD80 expressed

  11. Mechanism of hapten-carrier effect Ag BCR BCR BCR BCR MHC B cell B cell B cell B cell TCR Th cell • Activated Th2 produce cytokines and CD40L • CD40L interacts with CD40 = signal 2 • Cytokines drive proliferation and differentiation of Bs CD28 CD80/86 CD40L 4. Cytokine binds R CD40L binds CD40 Bs activation 3. 5. Th activated, express CD40L, cytokine release B cell proliferate, differentiate, secrete Ig cytokines

  12. Cell-cell interactions in 1° Ab response Ag Ag 1. BCR Th primed by APC MHC B cell TCR TCR Th cell Th cell • Bs are not best APC in 1° Ab response • DC and macrophage • Th cells can be primed by other APC before interaction with Bs Th signals B Bs proliferate, differentiate, secrete Ig 2. CD28 CD80/86 MHC APC CD28 CD80/86

  13. Cell-cell interactions in 2° Ab response • Memory Bs and memory Ts created during 1° response • Bs have high affinity Ig receptor • Can take up Ag at lower concentrations than other APCs that lack Ig R • Memory Ts more easily activated than naïve • B-T interaction is sufficient to generate 2° Ab response

  14. Cytokines and class switching • Th cell cytokines stimulate B cell proliferation and differentiation • Cytokines also regulate the class of Ab

  15. Cell-cell interactions inAb responses Responses to exogenous Ag T-independent Ag

  16. Cell-cell interactions in response toT-independent Ag • Cell-cell interactions do not occur • Activation of Bs without class II self MHC-restricted T help • Polymeric nature of these Ags allows for cross-linking of Ag receptors on Bs • No 2° response, affinity maturation, or switch • Response dominated by CD5+ Bs

  17. CD5+ B cells • CD5+ Bs (B1 cells) • Distinct from conventional Bs (B2 cells) • First to appear in ontogeny • Express surface IgM, little or no IgD • Produce IgM from minimally mutated germline • Ab are low affinity and polyreactive • Account for most of IgM in adult serum

  18. CD5+ B cells • Properties (continued) • Do not develop into memory Bs • Self-renewing: do not continue to arise from bone marrow like conventional Bs • reside in peripheral tissues • Predominant Bs in peritoneal cavity • Significance • Major defense against pathogens with polysaccharide in cell wall • Individuals with T defects can still resist many bacterial infections

  19. Cell-cell interactions incell-mediated immune response:Generation of CTL Responses to endogenous Ag in cytosol Killing of virus-infected and transformed cells

  20. Cytotoxic T cells • CTLs are not fully mature when exit thymus • TCR recognizes Ag in MHC context • Cannot kill • Must differentiate to fully active CTL • Therefore, are “pre-CTL”

  21. 1. Generation of CTL Ag Stimulator cell presents Ag in MHC class I to CD8+ pre-CTL stimulator CD80/86 MHC Class I CD28 • Differentiate in response to: • Specific Ag in MHC • Cytokines from Th1 Ts CD4+ Th cell MHC Class II TCR Ag APC TCR 3. CD8+ pre-CTL 2. Pre-CTL differentiates to functional CTL cytokines Th releases IFN-γ, IL-2 APC presents Ag in MHC II to CD4+ Th cell

  22. Features of CTL • Ag specific • Target must bear the same Ag in MHC class I as the stimulator cell • Requires cell contact • Ensures that nearby cells are not killed • CTLs are capable of killing many targets • They are not “damaged” when they kill a target

  23. Mechanisms of CTL killing • Fas and TNF-mediated killing • FasL on CTL binds FasR • TNF secreted by CTL binds TNFR on target • L binding trimerizes R • R with death domain activates caspases to signal apoptosis

  24. Mechanisms of CTL killing • CTL granule-mediated killing • perforin & granzymes released from CTL granules • Perforin polymerizes and forms channels in membrane • Granzymes (serine proteases) enter through channel, activate caspases

  25. Cell-cell interactions in cell-mediated immune response: activation of macrophages Responses to endogenous Ag in vesicles Killing of intracellular pathogens in vesicles

  26. Central role of macrophage inspecific immune response Macrophage Macrophage Macrophage • Initial defense • Innate, nonspecific immune response • Ag presentation • Activation of Th • Effector functions • Cytokine production • Anti-microbial • Anti-tumor Infecting agent Ag presentation Activated macrophage TCR MHC Class II T cell cytokines Ag Activate Cytokines Anti-microbial Anti-tumor lymphokines

  27. Effector function of activated macrophages • Pneumocystis carinii • Extracellular fungal pathogen • Controlled by activated macrophage • In AIDS patients infection commonly causes death • Mycobacterium tuberculosis • Intracellular pathogen, resides in vesicles • Not killed unless macrophages are activated • Again, problem for AIDS patients

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