Immunoregulation

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Immunoregulation

• Jennifer Nyland, PhD
• Office Bldg1, Room B10
• Phone [phone]
• Email jnyland_at_uscmed.sc.edu

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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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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

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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)

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Regulation in response to Ag

• Dose (and route) of Ag exposure- see Ag lecture

Virus dose (pfu) Antiviral cytotoxicity Th1 response (IFN?) Th2 response (IL-4)
0.3
1000
120 80 40 0
40 80 120
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Regulation by Ab

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

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Regulation by Ab

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

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Regulation by Ab

• Activation
• Ab/Ag immune complex bind complement (C3d),
  localize to APC via complement R ? maintained
  source of Ag

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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

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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

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Regulation by Tregs

• Types of Tregs Naturally arising
• Thymus gives rise to CD4CD25Foxp3 Treg
• CD25 part of IL-2R
• Foxp3 transcription factor, defects ?
  autoimmune and inflammatory disease
• Suppress in cell-cell dependent manner
• Mechanism unknown

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Regulation by Tregs

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

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Regulation by Tregs

• Types of Tregs CD8 Tregs (CTL2 cells)
• release a spectrum of cytokines similar to Th2
  cells IFN-?, 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

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Genetic factors

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