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1、1.Induction of Th17 and Tregs,Th17 ：CD4+ T cells which produce IL-17 play an important role in promoting chronic inflammation and autoimmune diseases Treg-regulatory T cell： A population of T cells that regulates the activation of other T cells and is necessary to the maintain peripheral tolerance t
2、o self antigens. Inhibit autoimmunity prevent transplant rejection Interfere with anti-cancer immunity Potential in immune deficiency,Conception: Tregs and Th17,I. Types of regulatory T cells,CD4+ Regulatory T cells: CD4+CD25+ T cells CD8+ Regulatory T cells: CD8+CD28-T cells or Qa-1- restricted CD8
3、+ NK T cells: CD3+NK1.1 T cells Double negative regulatory T cell: CD3+CD4-CD8-,II. Discovery and development of Regulatory T cells,1. Discovery of suppressor T cells Richard Gershon at Yale University in 1971 demonstrated firstly that suppressor T cells may be critical to the control of virtually a
4、ll immune responses arose in the laboratory in studies of infectious immunological tolerance.,Gershon, R.K., and Kondo, K. 1971. Infectious immunological tolerance. Immunology. 21:903-914.,Anti-A antibody,Conception of suppressor T cells,2. Discovery of CD8+ suppressor T,Discovery of suppressor CD8+
5、 T cells Cantor, H., and Boyse, E.A. 1975. Functional subclasses of T-lymphocytes bearing different Ly antigens. I. The generation of functionally distinct T-cell subclasses is a different process independent of antigen. J. Exp. Med. 141:1376-1389 Cantor, H., and Boyse, E.A. 1975. Functional subclas
6、ses of T lymphocytes bearing different Ly antigens. II. Cooperation between subclasses of Ly+ cells in the generation of killer activity. J. Exp. Med. 141:1390-1399,Moller, G. 1988. Do suppressor T cells exist? Scand. J. Immunol. 27:247-250 Reasons : Lack of enough evidence( No clone was established
7、 and no marker for Ts was discovered ),(2) Suspicion to suppressor T cells,Jiang, H., Zhang, S.I., and Pernis, B. 1992. Role of CD8+ T cells in murine experimental allergic encephalomyelitis. Science. 256:1213-1215. Koh, D.-R. et al. 1992. Less mortality but more relapses in experimental allergic en
8、cephalomyelitis in CD8/ mice. Science. 256:1210-1213.,(3)The resurrection of CD8+ suppressor T cells,Jiang, H ,Science. 256:1213-1215.,CD8 T cells have inhibitory function,Classification of T cells CD4+ : Th CD8+: Tc :cytotoxicity Ts :suppressor,3. Discovery and rapid rise of CD4 suppressor T cells,
9、(1)Discovery of CD4 suppressor T cells by Thomas, Y in 1980 Thomas, Y. et al. 1980. Functional analysis of human T cell subsets defined by monoclonal antibodies. I. Collaborative T-T interactions in the immunoregulation of B cell differentiation. J. Immunol. 125:2402-2408,Sakaguchi, S., Fukuma, K.,
10、Kuribayashi, K., and Masuda, T. 1985. Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. J. Exp. Med. 161:72-87,Sakagu
11、chi and colleagues (1985) These thymectomized mice were shown to have reduced numbers of CD4+ as well as CD8+ T cells and develop the organ-specific autoimmune disease Furthermore, reconstitution of thymectomized mice by highly enriched populations of CD4+ but not CD8+ T cells from syngeneic normal
12、mice completely inhibited disease development,(2). Discovery of CD4 suppressor T cell marker-CD25,1995, Sakaguchi showed for the first time that the suppression mediated by CD4+ T cells is a function of the small subset of CD4+CD25+ cells,Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M., and Toda,
13、M. 1995. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155:1151-1164,The transfer of T cells depleted in the CD4+CD25+ population into nude (at
14、hymic) mice led to a variety of autoimmune diseases, which could be prevented by injection of purified CD4+CD25+ T cells but not CD4+CD25 T cells. The field of CD4+CD25+ regulator cells, termed “CD4+CD25+ Tregs,“ was thus born and has experienced an explosive growth over the past few years,(3) Disco
15、very of CD4 regulatory T cell specific marker Foxp3,Fontenot, J.D., Gavin, M.A., and Rudensky, A.Y. 2003. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4:330-336 Hori S,1 Nomura T,2 himon, Sakaguchi S1 Control of Regulatory T Cell Development by the Trans
16、cription Factor Foxp3 Science, 299( 5609):1057-1061, 14 February 2003,Rudensky, A.Y,Sakaguchi, S,IV. CD4+CD25+Treg,I) Types of CD4+CD25+ T reg,nTreg: naturally occurring CD4+CD25+ Treg iTreg: induced CD4+CD25+ Treg Tr1(IL-10) , Th3 , TGF-induced, Foxp3+ Treg,Types of CD4+CD25+Treg-nTreg and iTreg,Na
17、turally occurring Treg,induced Treg,II). Phenotype Marker of CD4+CD25+Treg,CD25+ Foxp3:a master control gene for Treg development CTLA4 : cytotoxic T lymphocyte antigen-4 GITR: glucocorticoid -induced TNF receptor familyrelated gene or CD152) CD45RBlow, CD62L, CD103, Neuropilin-1 IL-2 is essential f
18、or the development, maintenance, and function of CD25+CD4+ Tregs,1. Foxp3 is a kind of transcript factor Foxp3 -deficient mice leads to lymphocytes proliferation diseases,2. Foxp3 expression is predominantly restricted to the CD25+CD4+ population in both the thymus and periphery.,3. CD4+CD25+ T cell
19、s from Foxp3-/-mice lack regulatory function,Foxp3-/- CD4+CD25+ has no regulatory function Transfer of CD4+CD25+ Treg from wt mice rescue Foxp3 deficiency Foxp3-transfected CD4+CD25-T cells obtain Regulatory function,4. Suppressive activity of Foxp3-transduced nave CD4+ T cells,III) characteristics
20、of natural CD25+CD4+ Tregs and their mechanisms of suppression,1.Origin: Thymus The normal thymus produces the majority, if not all, of CD25+CD4+ Tregs as a functionally mature T cell subpopulation in Thymus,2.Constitute 510% of CD4+ T cells in normal naive mice,CD25+CD4+ Tregs themselves are anergi
21、c in vitro they do not proliferate or not produce IL-2 in response to conventional T cell stimuli such as plate-or beadbound anti-CD3, ConA, or splenic APCs. Inhibit other immune cells the most remarkable feature of CD25+CD4+ Tregs is their ability to dampen immune responses suppressing a wide varie
22、ty of immune cells : the innate and the adaptive immune systems,3. Functional features,4. CD25+CD4+ Treg suppression mechanism,Cell-cell contact suppression: CTLA4-B71(CD80) Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S. CTLA-4 control over Foxp3+ regul
23、atory T cell function. Science. 2008 Oct 10;322(5899):271-5 Release cytokines : IL-10, TGF-,IV) Induced CD4+CD25+ Tregs,1. Types of Induced CD4+CD25+ Treg 1) Tr1 2) Th3 3) induced Foxp3+Treg,Tr1 cells were initially generated by chronic stimulation of normal nonregulatory T cells in the presence of
24、IL-10 Tr1 cells are functionally suppressive in vivo and able to prevent the development of Th1 autoimmune diseases such as colitis Groux, H. et al. 1997. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature. 389:737-742.,(1) Tr1（T regulatory cell type 1 ）,Clo
25、ned from the mesenteric lymph nodes of mice orally tolerized with myelin basic protein (MBP) The majority of such cells produce TGF-, suppress the induction of experimental autoimmune encephalomyelitis （EAE) Chen, Y., Kuchroo, V.K., Inobe, J., Hafler, D.A., and Weiner, H.L. 1994. Regulatory T cell c
26、lones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science. 265:1237-1240,2). Th3 cells : TGF-,陈有海,Youhai Chen: discoverer of Th3,Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction Chen, W. et al. 2003.Conversion of perip
27、heral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J. Exp. Med.,3). Foxp3+ Treg: TGF-beta-induced Treg,Wanjun Chen : discover of TGF-iTreg,TGF- beta converts nave CD4+CD25- T cells to CD4+CD25+anergy T cells,TGF- beta -converted CD4+CD2
28、5+ T cells express Foxp3,TGF- beta-induced CD4+CD25+ T cells inhibit allergic disease,mite,1) Cytokines: TGF-beta, L-10 2) Immature DC 3) “low-zone ”antigen,2 Factor inducing development of CD4+CD25+ Treg,V) Function and clinical significance of CD4+CD25+ Treg,1.Physiological function key controller
29、s of self tolerance. 2. Clinical significance Inhibit autoimmunity prevent transplant rejection Interfere with anti-cancer immunity Potential in immune deficiency,Characteristics of CD4+CD25+Tregs,In vivo Maintain immune tolerance Inhibit autoimmunity prevent transplant rejection Interfere with anti
30、-cancer immunity Potential in immune deficiency,In vitro 5-10% of CD4+ T cells Anergic to TCR stimulation Suppress T cell proliferation,CD4,CD25,Foxp3,FACS,CD25,CD25,Foxp3,Microscopy,Co-culture,10%,90%,Function of CD4+CD25+Treg,Maintains the homestasis,Infectional disease: HBV infection Transplantat
31、ion rejection: Treg Autoimmune diseases: RA Tregs,Tumor: Treg,Be Be involved in several diseases,The decrease of Treg in peripheral blood of Acute Coronary Syndrome,Transplantation rejection: Treg Autoimmune diseases: SLE and RA Tregs,Tumor: Treg,Be Involved in several diseases,The increase of Treg
32、in spleen and lymph node tumor-loading mice,3.2%,3.1%,4.9%,9.0%,9.6%,The increase of Treg in peripheral blood and tumor-infiltrated lymph node of patient with tumor,Patients with esophageal cancer,LN,PBMC,CD4+CD25+Treg cells and diseases,Transplantation rejection: Treg Autoimmune diseases: SLE and R
33、A -Tregs Tumor: Treg,How to get the enough Treg cells for the treatment?,How to delete or decrease Tregs?,V. CD8+ Regulatory T cells,I) Classification CD8+CD28- T regulatory T cells Qa-1 restricted CD8+ regulatory T cells,II) Qa-1 restricted CD8 + regulatory T cells,1. Features of Qa-1 restricted CD
34、8 + regulatory T cells 1)CD8+ regulatory T cells are not naturally occurring cells but instead are specifically induced during the primary adaptive immune response 2) The CD8+ regulatory T cells in the control of autoimmune disease in vivo is only observed during the secondary, but not the primary,
35、immune response 3) Qa-1(MHC Ib) restriction but not MHC Ia restriction,paralysis,2. Mechanism of Qa-1 restricted CD8 + regulatory T cells,Regulation of CD8+ regulatory T cells: Interruption of the NKG2A-Qa-1 interaction allows robust suppressive activity and resolution of autoimmune disease. Lu L, K
36、im HJ, Werneck MB, Cantor H. Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19420-5. Epub 2008 Dec 1.,3. CD8+ T cell suppression and self tolerance Murine EAE Adjuvant-induced arthritis Mouse models of type 1 diabetes Qa-1specific transplantation tolerance could prevent generation of alloreactive CTL,
37、(III) nonQa-1restricted CD8+CD28 cells,Can suppress immune responses by directly interacting with antigen-presenting DCs and rendering these cells tolerogenic The suppression involves the upregulation of inhibitory Ig-like transcript 3 (ILT3) and ILT4 receptors expressed on the DCs. Specific unrespo
38、nsiveness in CD4+ T helper cells. The precise function of these cells in vivo is not clear, and it is not known whether they interact with the Qa-1restricted CD8+ suppressor cells or, alternatively, whether Qa-1restricted T cells induce tolerogenic DCs.,Reference,Chen, W. et al. 2003.Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J. Exp. Med Ait-Oufella H et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med. 2006 Feb;12(2):178-80. Epub 2006 Feb 5,