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Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002

Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002. The definition of the Th1/Th2 subsets. Situations in which Th subsets important. How do subsets arise and differentiate? Future directions with this paradigm. Related T cell subsets Regulatory T cell subsets.

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Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002

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  1. Th Cell SubsetsDale T. Umetsu, MD, PhDFebruary 27, 2002 • The definition of the Th1/Th2 subsets. • Situations in which Th subsets important. • How do subsets arise and differentiate? • Future directions with this paradigm. • Related T cell subsets • Regulatory T cell subsets.

  2. Expression of cytokines by CD4 T cell subsets Cytokine Th1 Th2 Th0 Thp IFN-g + - + - IL-4 - + + - IL-3 + + + - GM-CSF + + + TNF-a + + Lymphotoxin + - - IL-2 + - + + IL-5 - + + - IL-9 - + IL-10 - + - IL-13 - +

  3. Generation of Th Cell lines OVA + APC rIL-12 Anti-IL-4 mAb Th1 OVA + APC rIL-4 Anti-IL-12 mAb Isolate clonotypic CD4+ T cells Th2 OVA + APC rIL-4 rIFN-g Th0 DO11.10 OVA-specific TCR Tg

  4. Markers of Th1 and Th2 Cells Th1 Th2 IFN-, IL-2 IL-12R2 IL-18R P- and E- selectin receptor CXCR3, CCR5 Tim3 Stat4, T-bet IL-4 IL-1R, IFN- receptor T1/ST2 (homolog of IL-1R) CCR3, CCR4, CCR8 Tim1? ICOS GATA-3, Stat6

  5. Infection with Leishmania Strain result cytokines produced C3H/HeN resistant IFN-g, IL-2 BALB/c susceptible IL-4, IL-5, IL-13

  6. Disease States Attributed to an Imbalance in Th1/Th2 Cells Over production Over production of Th2 cytokines of Th1 cytokines Autoimmune diseases Multiple sclerosis Rheumatoid arthritis Diabetes mellitus Crohn’s disease Graft rejection Helminth infection Aborted pregnancy • Infections • Leishmania • TB, leprosy • Fungal infection • HIV • Allergy • Ulcerative colitis

  7. T Cell Subsets: when are they important? • During chronic antigen stimulation • Chronic infection • Chronic response to auto antigens. • Chronic exposure to allergens. • Not following a single antigenic stimulation, not with fulminant infections.

  8. Th1 Cells Cross Regulate Th2 Cells Th1 cytokines IL-2 IFN-g IL-12 Th2 cytokines IL-4 IL-5 IL-13 IL-4 IL-10 IL-12 IFN-g

  9. What are the instructive signals for the development of Th1/Th2 cells • Cytokine microenvironment • Antigen dose/TCR signaling • Altered peptide ligands • APC type • Route of antigen administration • Costimulatory signals • Host genetic factors

  10. Signals that influence Th differentiation IL-4, IL-10, TGF-b IL-12, TGF-b

  11. Antigen Effects • High antigen dose induces Th1 cell differentiation; low dose induces Th2 cell differentiation. • Peptides with high affinity for the TCR induces Th1 responses • Altered peptide ligands induce Th2 responses. • Peptide affinity for TCR alters phosphorylation of TCR associated proteins.

  12. Transcription factors that influence Th differentiation Innate immunity IL-12 T-bet c-maf GATA-3

  13. Agarwal, Rao. 1998. Immunity. 9:765

  14. Lafaille, et al. J. Exp. Med 186:307, 1997. Th1(5x106) Th2 (5x106) Th1(0.2x106) Th2(0.2x106)

  15. Attempts to tolerize with MOG results in exacerbation. Genain, et al. 1996. Science. 274:2054

  16. Transfer of diabetes with both Th1 and Th2 cells Pakala, et al. 1997. JEM. 186:299.

  17. Th1 cells do not inhibit Th2 cell-induced airway hyperreactivity Hansen, et al J.C.I. 1997

  18. The Th1/Th2 Paradigm and Disease Regulation • Both Th1 and Th2 cells cause disease. • The “opposite” of Th1 cells is not a Th2 cell. • The Th1/Th2 paradigm cannot fully explain immune regulation. • Additional regulatory cells must exist to regulate immune responses.

  19. Tr1 Cells • Develop after stimulation with IL-10. • Produce IL-10, IL-5, (TGF-b). • Inhibitory for experimental colitis. • Anti-IL-10 mAb reverses inhibitory effect. • Low proliferative capacity. • Mature DCs producing IL-10 induce Tr1 cells.

  20. Th3 Cells • Generated by oral tolerance induction with low dose antigen. • Produce TGF-b, IL-4 • Express regulatory/suppressive activity. • TGF-b production may be enhanced by cross-linking of CTLA-4.

  21. CD45RBlow Cells, CD25+ Cells • CD25+. • When transferred, have strong regulatory/suppressive activity for colitis and diabetes. • Appear to require TGF-b and IL-10 to function. • CTLA-4 signaling required. • Antigen specificity?

  22. 2000 high antigen uncommitted CD4+ T cell Th? Th2 Th3 Tr1 Th1 CD8 NK T cell CD45RBlow

  23. Summary-T cell subsets • A major theme in immunology, and documented feature of the immune system. • Subsets of T cells express restricted cytokine profiles • Cells with restricted cytokine profiles (CD4, CD8, NK, NK T, B) have distinct effector functions and regulate immune responses.

  24. Questions that remain • What regulatory cells “balance” Th1 and Th2 cells? What downregulates polarized responses? • How Th subsets are involved in tolerance? • What additional molecular mechanisms regulate cytokine synthesis? • What are the host/genetic factors that regulate cytokine production?

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