1 / 24

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.

jaafar
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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?

More Related