T helper subsets

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T helper subsets

• Penny Morel
• March 23, 2007
• 4-0343, morel_at_pitt.edu

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Outline

• Th cell subsets
• Role of DCs in determining T cell effector
  function
• Factors necessary for Th1/2 differentiation
• A new Th subset - ThIL-17
• Development and function of Treg in periphery

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Naïve CD4 T cells can differentiate into several
Teff and Treg types
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Immunol. Rev. 182207, 2001
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Th1/Th2/Th17 in disease
Agent/Disease Host Response Outcome Leishmanias
is M Th1 Cure Th2 Exacerbation Leprosy H
Th1 Tuberculoid Th2 Lepromatous RA/MS H
Th1 Th1 cells in lesion H Th17 Th17 in
lesions Allergy H Th2 Th2 cytokines in
lesion M Th17 Induces PMN Ac
GVHD M Th1 Th1 cytokines Chr
GVHD M Th2 Th2 cytokines
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Nature Rev. Immunol. 3984, 2003
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Dendritic cells and T cell effector function
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Th1/Th2 differentiation

• Arise from a common precursor
• Cytokines
• Antigen dose
• Costimulatory molecules
• Differentiation results in expression of master
  regulators GATA-3 for Th2 and T-bet for Th1

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Signaling molecules and transcription factors
important in Th1/Th2 differentiation Annu. Rev
Immunol. 21713, 2003
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• Knockout mice that have defects in Th1
  development
• IFN-?, IFN-?R, IL-12, IL-12R, Stat4, IRF-1,
  ICSBP, T-bet
• IL-12 is necessary for IFN-? production, and
  IFN-? is necessary
• for the induction of IL-12 responsiveness (acts
  via induction of T-bet)
• stimulates expression of the IL-12R ?? chain
  (signal transduction)
• IL-4 and IFN-??are mutually antagonistic in
  Th1/Th2 development
• Source of IL-12
• dendritic cells, macrophages. Certain pathogens
  stimulate
• secretion of large amounts of IL-12 by DC and
  macrophages
• Source of IFN-?
• NK cells, Th1 cells

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Knockout mice that have defects in Th2
development IL-4, IL-13, IL-4R, Stat6 GATA-3
antisense blocks Th2 development Source of
IL-4 Was thought to be either mast cells or CD4
NK1.1 T cells - but neither one was proven Now
thought to come from developing Th2 cells -
under the influence of IL-6, although IL-6 KO
mice can still make some Th2 responses. It is
possible that Th2 differentiation is the default
pathway in the absence of IL-12
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Cytokines influence Th1/Th2 differentiation
Science 260547, 1993
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Interleukin 4

• 20 kD protein produced by Th2 cells, mast cells,
  NKT cells
• Induces proliferation of T cells and
  differentiation of Th2 cells antagonizes Th1
  differentiation
• Induces the expression of GATA-3 transcription
  factor

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IL-4 receptor
Stat6
Annu. Rev. Immunol 17701, 1999
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Interleukin-12

• Heterodimeric cytokine IL-12p70 - formed by two
  chains IL-12p40 and IL-12p35 (encoded on
  different chromosomes)
• Produced by activated DC, macrophages
• Acts on NK and T cells to stimulate IFN-?
  production costimulates Th1 proliferation
  enhances NK cytotoxic activity induces Th1
  differentiation
• IL12-R has two chains ?? and ?2 signals through
  stat 4
• IL-12 p40 can form homodimers and inhibit the
  action of IL-12p70

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IL-12 and IL-23
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ThIL-17 cells

• Produce IL-17, IL-17F, IL-6, TNF
• IL-17 induces the production proinflammatory
  cytokines TNF, IL-1, IL-6, IL-8
• ThIL-17 cells have been found in the diseased
  tissues of patients with RA, Lyme arthritis, MS,
  SLE and asthma
• New data suggest that this is a distinct lineage
  - development may require IL-6 and TGF-?

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Cytokine requirements for ThIL-17
Nature 44 235 (2006)
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Antigen dose influences Th1/Th2 development Very
high and very low dose leads to Th2
response Intermediate dose leads to Th1
response Same pattern is not always seen in
complex antigens
Annu. Rev. Immunol. 1997. 15297-322.
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Role of DC subsets and antigen dose in the
differentiation of Th1 or Th2 cells J. Exp
Med. 197101. 2003
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Other molecules implicated in Th1/Th2
differentiation

• Costimulatory molecules CD86, B7-h bind to CD28
  and ICOS resp.
• OX40 (T cell)-OX40L (DC) - induced after
  activation, favor Th2
• Chemokines - differential expression of chemokine
  receptors of T cell subsets, different patterns
  of chemokine production by DC subsets

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New data suggest that OX40L may play a role in
inducing inflammatory cytokines (TNF) J. Exp.
Med. 2021213. 2005
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Regulatory T cells in the periphery

• Naturally occurring CD4 CD25 Tregs develop in
  thymus
• Tr1 cells - produce IL-10 induced following
  interaction with DC in presence of
  immunsuppressive cytokines
• Th3 cells - produce IL-10 and TGF-b, usually
  found at mucosal surfaces

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J. Immunol. 1716323, 2003
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Mechanisms of Suppression
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Also induces FoxP3 expression in CD4 CD25- T
cells JI 1766752, 2006
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Seminars in Immunology 16104, 2004
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Nature Immunol. 2816, 2001
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GITR may play a role
Nat. Rev. Immunol. 6613, 2006
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Picture likely to get even more complicated!