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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
Naïve CD4+ T cells can differentiate into several Teff
and Treg types
Th1/Th2/Th17 in disease
Agent/Disease Host Response Outcome
Leishmaniasis M Th1 CureTh2 Exacerbation
Leprosy H Th1 TuberculoidTh2 Lepromatous
RA/MS H Th1 Th1 cells in lesionH Th17 Th17 in lesions
Allergy H Th2 Th2 cytokines in lesion
M Th17 Induces PMNAc GVHD M Th1 Th1 cytokines Chr GVHD M Th2 Th2 cytokines
Th subset differentiation
• Arise from a common precursor• Cytokines• Antigen dose• Costimulatory molecules• Differentiation results in expression of master regulators - transcription factors
Nature Rev. Immunol. 3:984, 2003
Th1 differentiation:
IL-12 is necessary for IFN- production, and IFN- is necessaryfor 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
Knockout mice that have defects in Th2 development:IL-4, IL-13, IL-4R, Stat6GATA-3 antisense blocks Th2 development
Source of IL-4Was 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
Signaling molecules and transcription factors important in Th1/Th2 differentiation
Annu. Rev Immunol. 21:713, 2003
Cytokines influence Th1/Th2 differentiation
Science 260:547, 1993
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
IL-4 receptor
Annu. Rev. Immunol 17:701, 1999
Stat6
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
IL-12 and IL-23
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
• Development requires IL-6, IL21, IL-23 and TGF-
• ROR-t is the signature transcription factor
Cytokine requirements for ThIL-17
Nature 44: 235 (2006)
European Journal of Immunology, 2008Volume 38 Pages 2636 - 2649
European Journal of Immunology, 2008Volume 38, Pages 2636 - 2649
Copyright ©2008 American Society of Hematology. Copyright restrictions may apply.
Zhu, J. et al. Blood 2008;112:1557-1569
Induction of cytokine receptors in Th cell differentiation
Role of DC subsets and antigen dose in the differentiation of Th1 or Th2 cells
J. Exp Med. 197:101. 2003
Copyright ©2008 American Society of Hematology. Copyright restrictions may apply.
Zhu, J. et al. Blood 2008;112:1557-1569
Th2 differentiation at low antigen dose
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
Copyright ©2008 American Society of Hematology. Copyright restrictions may apply.
Zhu, J. et al. Blood 2008;112:1557-1569
Crossregulation during Th cell differentiation
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-, usually found at mucosal surfaces
• Induced Treg - induced in presence of TGF-express Foxp3
Mechanisms of Suppression
Seminars in Immunology 16:104, 2004
Nature Immunol. 2:816, 2001
