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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 diseasesTreg-regulatory T cell：A population of T cells that regulates the activation of other T cells and is necessary to the maintain peripheral tolerance to se
2、lf antigens.Inhibit autoimmunityprevent transplant rejectionInterfere with anti-cancer immunityPotential 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+NK T cells:CD3+
3、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 all immune responses a
4、rose 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+T cells Cantor,H.,and Boyse,E.
5、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 subclasses of T lymphocytes bearing different Ly antig
6、ens.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 and no marker for Ts was discovered),(2)Suspicion to suppressor
7、 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 encephalomyelitis in CD8/mice.Science.256:1210-1213.,(3)The resurrection of CD8+sup
8、pressor 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,(1)Discovery of CD4 suppressor T cells by Thomas,Y in 1980 Thomas,Y.et al.1980.Functional anal
9、ysis 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.,Kuribayashi,K.,and Masuda,T.1985.Organ-specific autoimmune diseases induced in mice by elimination of T cell
10、 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,Sakaguchi and colleagues(1985)These thymectomized mice were shown to have reduced numbers of CD4+as well as CD8+T cells and de
11、velop the organ-specific autoimmune disease Furthermore,reconstitution of thymectomized mice by highly enriched populations of CD4+but not CD8+T cells from syngeneic normal mice completely inhibited disease development,(2).Discovery of CD4 suppressor T cell marker-CD25,1995,Sakaguchi showed for the
12、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,M.1995.Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains(CD25).Breakdown of a single mechanis
13、m 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(athymic)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 fi
14、eld of CD4+CD25+regulator cells,termed CD4+CD25+Tregs,was thus born and has experienced an explosive growth over the past few years,(3)Discovery 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+regul
15、atory T cells.Nat.Immunol.4:330-336 Hori S,1 Nomura T,2 himon,Sakaguchi S1 Control of Regulatory T Cell Development by the Transcription 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+Tr
16、eg iTreg:induced CD4+CD25+Treg Tr1(IL-10),Th3,TGF-induced,Foxp3+Treg,Types of CD4+CD25+Treg-nTreg and iTreg,Naturally 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-4GITR:glucocorticoid-indu
17、ced TNF receptor familyrelated gene or CD152)CD45RBlow,CD62L,CD103,Neuropilin-1IL-2 is essential for 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
18、restricted to the CD25+CD4+population in both the thymus and periphery.,3.CD4+CD25+T cells 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 functi
19、on,4.Suppressive activity of Foxp3-transduced nave CD4+T cells,III)characteristics 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 5
20、10%of CD4+T cells in normal naive mice,CD25+CD4+Tregs themselves are anergic 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+Tre
21、gs is their ability to dampen immune responsessuppressing a wide variety 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
22、Z,Nomura T,Sakaguchi S.CTLA-4 control over Foxp3+regulatory T cell function.Science.2008 Oct 10;322(5899):271-5Release 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
23、nonregulatory T cells in the presence of IL-10Tr1 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)Tr
24、1（T regulatory cell type 1）,Cloned 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.Regu
25、latory T cell clones 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 pe
26、ripheral 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+CD25+T cells e
27、xpress 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 controllers of self tolerance.2.C
28、linical significance Inhibit autoimmunity prevent transplant rejection Interfere with anti-cancer immunity Potential in immune deficiency,Characteristics of CD4+CD25+Tregs,In vivoMaintain immune toleranceInhibit autoimmunityprevent transplant rejectionInterfere with anti-cancer immunityPotential in
29、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 Transplantation rejection:Treg Autoimmune dis
30、eases: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 in spleen and lymph node tumor-loading
31、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 RA-Tregs Tumor:Treg,How to get the enough
32、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 CD8+regulatory T cells 1)CD8+regulatory T cells are no
33、t naturally occurring cells but instead are specifically induced during the primary adaptive immune response2)The CD8+regulatory T cells in the control of autoimmune disease in vivo is only observed during the secondary,but not the primary,immune response 3)Qa-1(MHC Ib)restriction but not MHC Ia res
34、triction,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,Kim HJ,Werneck MB,Cantor H.Proc Natl Acad Sci U S A.2008 Dec 9;105(49)
35、:19420-5.Epub 2008 Dec 1.,3.CD8+T cell suppression and self tolerance Murine EAE Adjuvant-induced arthritisMouse models of type 1 diabetesQa-1specific transplantation tolerance could prevent generation of alloreactive CTL,(III)nonQa-1restricted CD8+CD28 cells,Can suppress immune responses by directl
36、y 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 unresponsiveness in CD4+T helper cells.The precise function of these cells in vivo is not
37、 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.MedAit-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,
