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Immunoregulation

Immunoregulation. Jennifer Nyland, PhD Office: Bldg#1, Room B10 Phone: 733-1586 Email: jnyland@uscmed.sc.edu. Teaching objectives. To discuss regulation of immune responses including regulation by antibody, Tregs, and cytokines To discuss some genetic factors influencing immunoregulation.

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Immunoregulation

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  1. Immunoregulation Jennifer Nyland, PhD Office: Bldg#1, Room B10 Phone: 733-1586 Email: jnyland@uscmed.sc.edu

  2. Teaching objectives • To discuss regulation of immune responses including regulation by antibody, Tregs, and cytokines • To discuss some genetic factors influencing immunoregulation

  3. Regulation of immune responses • Magnitude of immune response determined by: • Ag-driven activation of lymphocytes • Negative regulatory influences that prevent or dampen response • Regulatory mechanisms act at all phases of immune response • Recognition • Activation • Effector function

  4. Regulation in response to Ag • Recognition: • in absence of co-stimulation → anergy (inability to respond) • Activation: • with CTLA-4 engagement of CD80/CD86 → down regulation of Ts (dampens activation) • Effector function: • Too much Ag → tolerance (induced state of unresponsiveness)

  5. Regulation in response to Ag • Dose (and route) of Ag exposure- see Ag lecture 120 80 40 0 40 80 120

  6. Regulation by Ab • Recognition: • Idiotype/anti-idiotype Ab interactions can stimulate or inhibit Ab responses • Ab blocking: Ab competes with B cells for Ag

  7. Regulation by Ab • Activation/Effector function: • Receptor cross-linking: Ag/Ab complexes binding to Fc receptors send inhibitory signal to Bs

  8. Regulation by Ab • Activation: • Ab/Ag immune complex bind complement (C3d), localize to APC via complement R → maintained source of Ag

  9. Regulation by cytokines • Cytokines are positive or negative regulators • Act at many stages of immune response • Dependent on milieu • Other cytokines and receptors • Regulate the type and extent of immune response generated

  10. Regulation by Tregs • Regulatory Ts (Tregs) do not prevent initial T activation • Inhibit sustained response • Prevent chronic and potentially damaging responses • Do not have characteristics of Th1, Th2, Th17 • Suppress Th1 and Th2 responses

  11. Regulation by Tregs • Types of Tregs: Naturally arising • Thymus gives rise to CD4+CD25+Foxp3+ = Treg • CD25 = part of IL-2R • Foxp3 = transcription factor, defects → autoimmune and inflammatory disease • Suppress in cell-cell dependent manner • Mechanism unknown

  12. Regulation by Tregs • Types of Tregs: induced Tregs • In the periphery some Ts induced to Treg • Requires Ag, IL-10, or TGF-β • IL-10: CD4+ CD25+ Foxp3- these are Tr1 • TGF-β: CD4+ CD25+ Foxp3+ • Ag: CD4+ CD25- Foxp3- • Suppress by secretion of: • Tr1 by IL-10 • Induced Treg by TGF-β • T effector memory cells by IL-2, IFN-γ, etc.

  13. Regulation by Tregs • Types of Tregs: CD8+ Tregs (CTL2 cells) • release a spectrum of cytokines similar to Th2 cells: IFN-γ, IL-6, IL-10 • Differentiation affected by CD4+ cytokine profile, Ag, and IL-10 • CD8+ Foxp3+ • Suppress in a cell-contact dependent manner • downregulation of co-stimulatory molecules on APC → tolerance • Primed by CD4+ during 1°, suppress during 2°

  14. Genetic factors • MHC-linked genes control response to infection • Certain HLA haplotypes are associated with responders/nonresponders, susceptibility/resistance • Cytokine and chemokine polymorphisms • Primarily in receptor genes • Non-MHC genes • Example, regulation of macrophage activity

  15. The Th1/Th2 paradigm IFN-γ inhibitory Cell-mediated immunity Humoral Immunity Th1 Th2 inhibitory IL-4, IL-10, TGF-β

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