1. Th 细胞亚群和 T 记忆细胞 季明春 扬州大学医学院 2010-12

2. 2 Th 细胞亚群 Th1/Th2 cells Th17 Cells Tfh Cells Th9 Cells Treg Cells

3. 3 Th 细胞亚群 Th1/Th2 cells Th17 Cells Tfh Cells Th9 Cells Treg Cells

4. 4 Introduction of Th1/Th2 cells In 1986, T.R. Mosman and R.L. Coffman observed that individual clones of mouse helper T cells could be separated into two classes depending upon the specific cytokines the cells secrete in response to antigenic stimulation.

5. Induction of Th1 and Th2 Responses Th2 Th1 Antigens IL-4 IL-12 IFN-γ APC Na ï ve CD 4 Effector Cells Signal 2 Signal 1 IL-2 IFN-γ IL-4 IL-5 IL-10 Cellular Immune Responses Humoral Immune Responses

7. 7 Th1 and Th2 Differentiation in vivo Infection of mice with Leishmania Major ( 利什曼原虫 ) provides a valuable model for the study of Th1 and Th2 differentiation in vivo

8. Leishmania major Infection in Mice Provides a Useful Model to Study Th1 and Th2 Differentiation and Memory in vivo

9. Leishmania major infection: Mouse Models Balb/C BL/6 Th 1 response Death Recovery Th 2 response IL-12 αIL-12/αIFN-γ

10. Signaling of IL-12 Receptor 11 22 TYK2TYK2 JAK2JAK2 p40 p35 STAT4STAT4 P P Y Stat4 P P Y Y IFN-  Production Expression  1: Expressed on Th1, Th2, N.K., and B cells  2: Expressed on activated Naïve T, Th1, and N.K. cells Regulation Enhanced by: activation of  -CD28, IL-2, IL-7, IL-15, IFN-  (mouse), IFN-  (human) Inhibited by: IL-4, IL-10, TGF- , PGE2, Dex

11. Cytokines On Th1 Cell Development Pathogen APC CD 4 + T Cell STAT4 TCR IFN-γ IFN-γ+++ IL-27 TCCR/ WSX-1 IL-12 IL-23 IL-12 IL-18 Naïve CD 4 + Th1 Th1 Effector IL-12Rβ1 β2 IL-18R IL-12Rβ1 β2 STAT1T-betIFN-γT-bet STAT4 NFKB GADD45 p3B IRAK NFKB

12. 12 The Th1/Th2 Paradigm in Human Diseases (1) Transplantation rejection and tolerance Th1—DTH—rejection Th2—tolerance Successful pregnancy and unexplained recurrent abortion Successful pregnancy Th2/Tho Recurrent abortion—Th1 Allergic disorders Th2 cells—the involvement of the mast cell/eosinophil/IgE-producing B cell in the pathogenesis of allergy

13. 13 The Th1/Th2 Paradigm in Human Diseases (2) Autoimmune disorders Autoimmune thyroid diseases—Th1 Multiple sclerosis (MS)—Th1 profile Th1 or insulin-dependent diabetes mellitus—Th1 profile Systemic sclerosis (SSc)—Th2 profile

14. 14 Th 细胞亚群 Th1/Th2 cells Th17 Cells—— IL-17-producing T cells Tfh Cells Th9 Cells Treg Cells

15. A new subset of Th cells — Th17 Naïve CD4 + T cell TGF- β IL-4 IL-23 IL-6 Th17 Th1 Th2 Treg IL-6 IL-17A IL-17B TGF- β IL-13 IL-4 IL-5 IL-12 IFN- γ (-)

16. T(H)-17 differentiation: of mice and men Nat Immunol. 2007, 8(9):903-5

17. 17 Th17 and diseases Infection Tumor Autoimmune disease Rheumatoid Arthritis(RA) SLE Multiple Sclerosis(MS)

18. 18 Th 细胞亚群 Th1/Th2 cells Th17 Cells Tfh Cells —— Follicular B helper T cells Th9 Cells Treg Cells

19. 19 Lose expression of CXCR5 Naïve T cells: CXCR5 - CXCR5 is transiently upregulated on CD4 + T cells following activation Retain CXCR5 expression Th1/Th2 Th17/Treg differentiation T FH cells Origin of T FH cells

20. Follicular helper T cells: Lineage and location Immunity 30, March 20, 2009 First contact between pMHC Ⅱ -specific effector T FH cells and antigen- primed pMHC Ⅱ + B cells occurs at the T-B borders. Pre-GC effector T FH cells

21. 21 T FH cells and autoimmunity  Human SLE patients : an increased frequency of ICOS + CD4 + T cells in their peripheral blood.  Lupus-prone mice: an increased frequency of ICOS + CD4 + T cells in spleens.  Chronic inflammation: T FH cells may also promote chronic inflammation. Any dysregulation of T cell function or tolerance induction can have a significant effect on the selection of Ab specificities:

22. 22 T FH cells and immunodeficiencies Ineffective T cell help to B cells appears to underlie certain humoral immunodeficiencies.  X-linked lymphoproliferative disease (XLP)  ICOS deficiency  CVID It is likely that compromised development or function of T FH cells contributes to impaired B cell differentiation and humoral immunity in conditions of immunodeficiency.

23. 23 Th 细胞亚群 Th1/Th2 cells Th17 Cells Tfh Cells Th9 Cells —— IL-9-producing T cells Treg Cells

24. 24 Introduction Recently, two reports described a discrete subset of interleukin-9(IL-9)-producing T cells that might be closely related to the T H 2-cell lineage. These IL-9-producing T cells seem to be a distinct population that does not show the characteristics of other described T-cell subsets------ “ T H 9 ” cells.

25. TGF-β deviates T H 2 cells to a “ T H -9 ” fate IL-9-producing T cells could be generated from T H 2 cells that were exposed to TGF-β in vitro, even when the T H 2 cells were highly polarized. × IL-4 inhibits TGF-β-induced Foxp3+ T cells IL-4 actively inhibits the induction of Foxp3 in the presence of TGF-β. The inhibition of Foxp3 expression by IL-4 is mediated through the IL-4-STAT6 pathway. The Foxp3 can directly interact with GATA-3 and this association inhibits GATA-3 mediated transactivation of IL-5, which is one of its target genes.

26. 26 Function of IL-9 + T cells IL-9 is involved in immunity against helminths and is important for recruiting mast cells to the site of infection. Lower levels of IL-9 production correlated with decreased mast-cell recruitment and impaired immunity against the helminth Trichuris muris.

27. 27 T H 9 cells lack suppressive function and promote tissue inflammation. ◆ T H 9 cells also produced IL-10. However, unlike IL- 10-producing Tr1 cells,T H 9 cells do not have any suppressive effects in vitro but readily proliferate and thus act like effector T cells. ◆ Adoptive transfer of IL-9 + IL-10 + T cells into recombination- activating gene 1-deficient mice induced colitis and peripheral neuritis, the severity of which was aggravated if the IL-9 + IL-10 + T cells were transferred with CD45RB hi CD4 + effector T cells. Function of IL-9 + T cells

28. 28 Th 细胞亚群 Th1/Th2 cells Th17 Cells Tfh Cells Th9 Cells Treg Cells —— Suppressor or Regulatory T Cells

29. 29 Introduction Regulation of immune responses to self-antigen is a complex process –Maintaining self-tolerance –Retaining the capacity to mount immune responses against invading microorganisms

30. 30 Discovery of Suppressor T Cells In 1995, Sakaguchi et al made the seminal observation: The transfer of CD4+ T cells which had been depleted of the minor subpopulation (10%) of cells to nu/nu recipients induced organ- specific autoimmune diseases in the majority of recipients. The minor subpopulation of cells are CD4+CD25+ T cells.

31. 31 CD4 + CD25 + Tr cells Constitutively express the IL-2R-α (CD25) Glucocorticoid induced tumor necrosis factor receptor (GITP) 5-10% of the peripheral T cell pool The regulatory effect by a mechanism dependant on cell- cell contact Expression of the inhibitory co-stimulatory molecule CTLA-4 Cell surface TGF-β or release IL-10 Foxp3, master regulatory gene

32. Overview of phenotypes and functions of CD4 + T cells Naïve CD4 Th1 Tr Th2 IFN-γ Cell mediated immune responses IL-4 IL-5 IL-10 IL-13 humoral immune response Tr 1 Th 3 CD4 + CD25 + High IL-10, low TGF-β TGF-β cell-cell contact Natural Tr in thymus contact-dependent Adaptive Tr in peripheral lymphoid tissue cytokines- dependant Regulatory T cells

33. Differentiation of Tr cells Naïve CD4 + T cells Tr1 Th3 CD4 + CD25 TGF-β IL-10 + IFN-α _

34. 34 Primary function of Tr cells Maintaining self-tolerance and homeostasis Preventing infection-induced immunopathology Prolong pathogen persistence by suppressing protective Th1 responses

35. 35 Generation of Tr1 cells OVA-TCR Naïve CD4 Tr1 cells IL-10 IL-5 +TGF-β OVA + IL-10 Immunosuppressive drugs Anti-IL-4 + Anti-IL-12

36. Phenotype and function of Tr 1 cells Expression CCR5 and TS-STL Immunosuppressive properties: - prevent the development of Th1 mediated autoimmune disease - suppress immune response to pathogens, tumors and allo antigens - suppress of proliferative responses and cytokine production The suppressive effects of Tr1 cells are reversed by neutralizing IL-10

37. 37 Th3 cells Secrete TGF-β Suppress the induction of experiment autoimmune encephalomyelitis (EAE). Suppress the induction of protective tumor-specific cytotoxin T lymphocyte (CTL) responses

38. What is the target cell for CD25+ T-cell-mediated suppression?

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42. 记忆性 T 细胞 Memory T cell Differentiation and Memory Generation

43. Immune response and generation of memory cells

44. 44 Phase of memory

45. Generation of CD4+ effector T cells

46. Subsets of Th1 cells with different cytokine profiles are related to protection and memory cell generation CCR7 + ( central memory cells ) secondary stimulation IFN-γ-producing cells ● Lower in expression of CCR7, Effector memory cells ● Mediating protection against infections ● Apoptosis ● Would be more limited in mediating optimal and sustained protection ● Apoptosis ● Reservoir of long-term central memory cells ● Unlikely to the sufficient for optimal protection

47. Generation of CD8+ effector T cells

48. Characterization of na ï ve, effector and memory T cells in humans

49. Characterization of na ï ve and memory T cells by the expression of surface molecules

50. 50 Differentiation model for memory T cells(1)

51. 51 Differentiation model for memory T cells(1)

52. 52 Differentiation model for memory T cells(1)

53. 53 Concept of memory The ability to remember the specific antigen and generate faster, stronger response against re-infection More antigen-specific T cells Faster and greater response

54. 54 Features of memory Shorter latency period Faster response Higher magnitude Longer persistence time Key feature of immune system Basis for vaccine design