1 / 35

Regulatory T Cells and HIV Infection

Regulatory T Cells and HIV Infection. ผศ. ศักดิ์ชัย เดชตรัยรัตน์ ดร. พานทอง สิงห์บุตรา ห้องปฏิบัติการเอชไอวี แขนงวิชาภูมิคุ้มกันวิทยาคลินิก คณะเทคนิคการแพทย์ มหาวิยาลัยเชียงใหม่. Immune Responses. Adaptive Immune Response. How this is achieved?. Self-Tolerance.

pier
Download Presentation

Regulatory T Cells and HIV Infection

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. Regulatory T Cells and HIV Infection ผศ. ศักดิ์ชัย เดชตรัยรัตน์ ดร. พานทอง สิงห์บุตรา ห้องปฏิบัติการเอชไอวี แขนงวิชาภูมิคุ้มกันวิทยาคลินิก คณะเทคนิคการแพทย์ มหาวิยาลัยเชียงใหม่

  2. Immune Responses

  3. Adaptive Immune Response How this is achieved?

  4. Self-Tolerance • The immune system discriminates between self and non-self • Establishing and maintaining unresponsiveness to self • Central Tolerance (clonal deletion) • Occurs within central lymphoid organs • Before lymphocytes mature • Peripheral Tolerance • Occurs in peripheral lymphoid organs • After lymphocyte mature

  5. Proposed Mechanisms of Peripheral Tolerance • Rendered anergic or further deleted if encounter self-antigen in the periphery • Fail to be activated because of low avidities to self-antigens • Lack of co-stimulation from APCs • Secluded from target self-antigens • Regulatory T cells actively down-regulate the activation and expansion of self-reactive lymphocytes

  6. Regulatory T Cells (Tregs) • “Suppressor cells” (Gershonet al. 1972) • CD4+ T cells that express the IL-2 receptor α chain control autoreactive T cells in vivo (Sakaguchiet al. 1995) • Antigen-specific T-cell clones suppressed the proliferation of CD4+ T cells in response to antigen and prevented colitis in a severe combined immunodeficiency mouse model (Grouxet al., 1997)

  7. Regulatory T Cells (Tregs) • Identification of several types of Tregs • “Regulatory T cells” is a preferred term

  8. Types of Tregs Levi G., et al. Seminars in Immunology. 2011. in press.

  9. CD4+CD25+Foxp3+ Regulatory T Cells • Fundamental in controlling various immune responses • Discovered by Sakaguchiet al. • 5-10% of peripheral CD4+ T cells • Expressed high level of IL-2Rα (CD25), Foxp3 • Developed in thymus and present in healthy individuals from birth

  10. γδ Regulatory T Cells • Comprise 5% of total T cells in peripheral lymphoid tissues • Enriched in skin, intestine and genito-urinary tract

  11. Natural Killer T Cells (NKT) • Produce large amount of Th1 (IFN-γ, TNF-α) and Th2 (IL-4, IL-10 and IL-13) cytokines • Play roles in tumor rejection, resistance to pathogenic infection, autoimmune diseases and allograft acceptance

  12. Regulatory T Cells Type 1 (Tr1) • Arise in the periphery following activation of naïve T cells with Ag in the presence of IL-10 • Produce • high IL-10, TGF-β and IL-5 • low IL-2 and IFN-γ • no IL-4 • Do not express high levels of either CD25 or Foxp3

  13. T Helper 3 (Th3) • Induced in gut environment with high TGF-β, Th2 cytokines, subsets of DC and oral antigens • Produces TGF-β • Induces tolerance to nonpathogenic resident bacteria and food antigens

  14. CD8+ Regulatory T Cells • Arise either from thymus or in response to foreign or self antigens • CD8+CD25+ share similar phenotypes and functions with CD4+CD25+ T cells • Express increased mRNA levels of Foxp3, GITR, CCR8, TNFR-2 and CTLA-4 • Following activation, express TGF-β1 and CTLA-4, do not produce cytokines

  15. Doble Negative T Cells (DN) • CD4-CD8-CD3+ comprised 1-2% of total CD3+ T cells in blood and lymph nodes • Express a unique set of cell surface markers • TCRαβ, CD25, LFA-1, CD69, CD45, CD30, CD62L and CTLA-4 • Produce • High IFN-γ • Low IL-10 and IL-4 • No IL-2

  16. Functions of Tregs

  17. HIV Infection • Loss of CD4+ T cells • Chronic immune activation • Progressive immune disfunction • Impaired immune responses

  18. Possible Roles of Treg in HIV Infection resistant to infection establish infection T cell T cell Quiescent Activated

  19. Possible Roles of Treg in HIV Infection • destruction of T cells • deterioration of immune function T cell T cell Loss of Treg Hyperactivation • No protective immune responses • Establish carrier state of infection • Expand of Treg • Excessive Treg activity Suppressed

  20. Changes in Treg Numbers in HIV Disease

  21. Changes in Treg Numbers in HIV Disease

  22. Treg Function in HIV Infection

  23. How to Identify Tregs?

  24. What are these markers? CD4 • A single chain molecule on T-helper cell • Binds to 2 domain of MHC-II • Increase the sinsitivity of T cell to Ag CD25 • Interleukin-2 receptor α-chain (IL-2Rα) • Receptor for IL-2, T-cell growth factor

  25. What are these markers? Foxp3 • Forkhead ⁄ winged-helix transcription factor box P3 • Transcriptional repressor • Most specific Treg marker currently • Key factor in controlling Treg development

  26. What are these markers? • Cytotoxic T lymphocyte associated protein-4 • Binds B7.1 (CD80)/B7.2 (CD86) • Major negative regulator of T-cell responses CTLA-4 (CD152)

  27. What are these markers? GIRT • Glucocorticoid-induced tumor necrosis factor receptor • Required for the induction of apoptosis • Expressed on various lymphocytes at different levels • High surface expression of GITR is only confined to resting nTreg cells in the periphery and thymus

  28. What are these markers? IL-7Rα (CD127) • Specific receptor chain for IL-7 • IL-7 control thymopoiesis and homeostasis of peripheral T lymphocytes

  29. %Cell Expressing Treg Markers

  30. Detection of nTregs

  31. FACS profile of CD4+CD25+ Cells

  32. FACS profile of CD4+CD25+ Cells

  33. FACS profile of CD4+Foxp3+ Cells Foxp3 Foxp3 CD4 CD4 Isotypes control

  34. FACS profile of CD25+Foxp3+ Cells

  35. Challenges in Identification of Tregs • Current markers are not truelyTreg-specific • All T cells express CD25 upon activation • CTLA-4 is upregulated on all CD4+ and CD8+ T cells, 2–3 days following activation • GITR is induced in T cells upon activation • CD127 is downregulated in most CD4+ T cells upon activation • Most human CD4+ and CD8+ T cells transiently express Foxp3 upon activation • Isolation of Treg using Foxp3 is limited to only phenotypic study

More Related