臨床検査55巻11号

2011年10月発行

特集 ここまでわかった自己免疫疾患 総論

7．制御性T細胞の機能と意義

著者： 西尾純子¹

所属機関： ¹東京大学大学院医学系研究科病因病理学専攻免疫学講座

ページ範囲：P.1099 - P.1112

制御性T細胞(Treg細胞)は，末梢性免疫寛容を維持するうえで，極めて重要な細胞である．Treg細胞は，自己免疫のみならず，炎症や感染，腫瘍においても，制御作用を発揮している．Treg細胞に特異的に発現しているFoxp3遺伝子は，Treg細胞の分化とともに抑制作用にも不可欠である．Treg細胞の大部分は胸腺で分化したnatural Treg細胞である一方，末梢ナイーブCD4T細胞がFoxp3を発現した細胞をinduced Treg細胞という．Treg細胞を介する抑制の低下が自己免疫疾患の発症にかかわっている可能性があり，注目されている．

参考文献

1) Sakaguchi S, Takahashi T, Nishizuka Y : Study on cellular events in post-thymectomy autoimmune oophoritis in mice. II. Requirement of Lyt-1 cells in normal female mice for the prevention of oophoritis. J Exp Med　156：1577-1586，1982

2) Hall BM, Jelbart ME, Gurley KE, et al : Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. Mediation of specific suppression by T helper/inducer cells. J Exp Med　162：1683-1694，1985

3) Kong YM, Giraldo AA, Waldmann H, et al : Resistance to experimental autoimmune thyroiditis : L3T4＋ cells as mediators of both thyroglobulin-activated and TSH-induced suppression. Clin Immunol Immunopathol　51：38-54，1989

4) Powrie F, Mason D : OX-22high CD4＋ T cells induce wasting disease with multiple organ pathology : prevention by the OX-22low subset. J Exp Med　172：1701-1708，1990

5) Sakaguchi S, Sakaguchi N, Asano M, et al : 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　155：1151-1164，1995

6) Bennett CL, Christie J, Ramsdell F, et al : The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3．Nat Genet　27：20-21，2001

7) Brunkow ME, Jeffery EW, Hjerrild KA, et al : Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet　27：68-73，2001

8) Chatila TA, Blaeser F, Ho N, et al : JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest　106：R75-R81，2000

9) Wildin RS, Ramsdell F, Peake J, et al : X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet　27：18-20，2001

regulatory T cells. Nat Immunol　4：330-336，2003

11) Hori S, Nomura T, Sakaguchi S : Control of regulatory T cell development by the transcription factor Foxp3．Science　299：1057-1061，2003

T regulatory cells. Nat Immunol　4：337-342，2003

13) Lio CW, Hsieh CS : A two-step process for thymic regulatory T cell development. Immunity　28：100-111，2008

immunoregulatory T cells that control autoimmune diabetes. Immunity　12：431-440，2000

15) Tai X, Cowan M, Feigenbaum L, et al : CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2．Nat Immunol　6：152-162，2005

16) Mantel PY, Ouaked N, Rückert B, et al : Molecular mechanisms underlying FOXP3 induction in human T cells. J Immunol　176：3593-3602，2006

17) Gupta S, Manicassamy S, Vasu C, et al : Differential requirement of PKC-theta in the development and function of natural regulatory T cells. Mol Immunol　46：213-224，2008

18) Medoff BD, Sandall BP, Landry A, et al : Differential requirement for CARMA1 in agonist-selected T-cell development. Eur J Immunol　39：78-84，2009

regulatory and natural killer-like T cells on signals leading to NF-κB activation. Proc Natl Acad Sci U S A　101：4566-4571，2004

20) Fontenot JD, Dooley JL, Farr AG, et al : Developmental regulation of Foxp3 expression during ontogeny. J Exp Med　202：901-906，2005

regulatory T cell development. J Immunol　181：3285-3290，2008

regulatory T cells by TGF-β induction of transcription factor Foxp3．J Exp Med　198：1875-1886，2003

T cells through Foxp3 induction and down-regulation of Smad7．J Immunol　172：5149-5153，2004

24) Apostolou I, Sarukhan A, Klein L, et al : Origin of regulatory T cells with known specificity for antigen. Nat Immunol　3：756-763，2002

regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants. J Immunol　172：6003-6010，2004

26) Kretschmer K, Apostolou I, Hawiger D, et al : Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol　6：1219-1227，2005

27) Mucida D, Kutchukhidze N, Erazo A, et al : Oral tolerance in the absence of naturally occurring Tregs. J Clin Invest　115：1923-1933，2005

T regulatory cells. J Immunol　184：3433-3441，2010

29) Atarashi K, Tanoue T, Shima T, et al : Induction of colonic regulatory T cells by indigenous Clostridium species. Science　331：337-341，2011

T cell receptors. Immunity　21：267-277，2004

T cells. Immunity　25：249-259，2006

T cells. J Immunol　178：7032-7041，2007

33) Rubtsov YP, Rasmussen JP, Chi EY, et al : Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity　28：546-558，2008

34) Collison LW, Workman CJ, Kuo TT, et al : The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature　450：566-569，2007

35) Grossman WJ, Verbsky JW, Barchet W, et al : Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity　21：589-601，2004

regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J Immunol　174：1783-1786，2005

regulatory T cells : independence of IL-2 consumption, TGF-β, and various inhibitors of TCR signaling. J Immunol　179：3578-3587，2007

38) Kobie JJ, Shah PR, Yang L, et al : T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5′-adenosine monophosphate to adenosine. J Immunol　177：6780-6786，2006

39) Deaglio S, Dwyer KM, Gao W, et al : Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med　204：1257-1265，2007

40) Fallarino F, Grohmann U, Hwang KW, et al : Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol　4：1206-1212，2003

regulatory T cells down-regulate co-stimulatory molecules on antigen-presenting cells. Eur J Immunol　30：1538-1543，2000

T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J Exp Med　202：1549-1561，2005

regulatory T cells modulate myeloid but not plasmacytoid dendritic cells activation. J Immunol　176：5293-5298，2006

T cells restrain the maturation and antigen-presenting function of dendritic cells. J Immunol　172：4676-4680，2004

45) Huang CT, Workman CJ, Flies D, et al : Role of LAG-3 in regulatory T cells. Immunity　21：503-513，2004

46) Liang B, Workman C, Lee J, et al : Regulatory T cells inhibit dendritic cells by lymphocyte activation gene-3 engagement of MHC class II. J Immunol　180：5916-5926，2008

47) Koch MA, Tucker-Heard G, Perdue NR, et al : The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol　10：595-602，2009

2 responses. Nature　458：351-356，2009

17 responses in a Stat3-dependent manner. Science　326：986-991，2009

50) Anderson MS, Bluestone JA : The NOD mouse : a model of immune dysregulation. Annu Rev Immunol　23：447-485，2005

51) Nishio J, Feuerer M, Wong J, et al : Anti-CD3 therapy permits regulatory T cells to surmount T cell receptor-specified peripheral niche constraints. J Exp Med　207：1879-1889，2010

52) Tang Q, Adams JY, Penaranda C, et al : Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity　28：687-697，2008

53) Tang Q, Henriksen KJ, Bi M, et al : In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med　199：1455-1465，2004

regulatory T-cells in type 1 diabetes. Diabetes　56：604-612，2007

regulatory T cell-mediated suppression in patients with type 1 diabetes. Clin Exp Immunol　154：353-359，2008

regulatory T cells. J Immunol　181：7350-7355，2008

regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J Immunol　169：4712-4716，2002

regulatory T cells in human autoimmune diseases. Nat Rev Immunol　10：849-859，2010

59) Gerli R, Nocentini G, Alunno A, et al : Identification of regulatory T cells in systemic lupus erythematosus. Autoimmun Rev　8：426-430，2009

60) Alvarado-Sánchez B, Hernández-Castro B, Portales-Pérez D, et al : Regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun　27：110-118，2006

T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol　178：2579-2588，2007

regulatory T cells in patients with active systemic lupus erythematosus. Arthritis Rheum　58：2120-2130，2008

63) Vargas-Rojas MI, Crispín JC, Richaud-Patin Y, et al : Quantitative and qualitative normal regulatory T cells are not capable of inducing suppression in SLE patients due to T-cell resistance. Lupus　17：289-294，2008

64) Morgan ME, Sutmuller RP, Witteveen HJ, et al : CD25＋ cell depletion hastens the onset of severe disease in collagen-induced arthritis. Arthritis Rheum　48：1452-1460，2003

T cells from the target organ of patients with rheumatoid arthritis. Eur J Immunol　33：215-223，2003

T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis. Clin Exp Immunol　140：360-367，2005

regulatory T cell population in peripheral blood. Rheumatology (Oxford)　45：1210-1217，2006

cells suppress innate immune pathology through cytokine-dependent mechanisms. J Exp Med　197：111-119，2003

regulatory T cells. J Exp Med　201：737-746，2005

regulatory T cells, Th17 effector cells, and cytokine environment in inflammatory bowel disease. J Clin Immunol　30：80-89，2010

71) Li Z, Arijs I, De Hertogh G, et al : Reciprocal changes of Foxp3 expression in blood and intestinal mucosa in IBD patients responding to infliximab. Inflamm Bowel Dis　16：1299-1310，2010

T cell survival. J Immunol　184：7247-7256，2010

T cells in inflammatory bowel disease. Gastroenterology　128：1868-1878，2005

T cells during cure of colitis. J Immunol　177：5852-5860，2006

75) Sitohy B, Hammarström S, Danielsson A, et al : Basal lymphoid aggregates in ulcerative colitis colon : a site for regulatory T cell action. Clin Exp Immunol　151：326-333，2008

76) Holt PG, Strickland DH, Wikström ME, et al : Regulation of immunological homeostasis in the respiratory tract. Nat Rev Immunol　8：142-152，2008

77) Sutmuller RP, Morgan ME, Netea MG, et al : Toll-like receptors on regulatory T cells : expanding immune regulation. Trends Immunol　27：387-393，2006

78) Urry Z, Xystrakis E, Richards DF, et al : Ligation of TLR9 induced on human IL-10-secreting Tregs by 1α,25-dihydroxyvitamin D3 abrogates regulatory function. J Clin Invest　119：387-398，2009

79) Hawrylowicz CM, O'Garra A : Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma. Nat Rev Immunol　5：271-283，2005

regulatory T cells reverse established allergic airway inflammation and prevent airway remodeling. J Allergy Clin Immunol　122：617-624，e6，2008

81) Hesse M, Piccirillo CA, Belkaid Y, et al : The pathogenesis of schistosomiasis is controlled by cooperating IL-10-producing innate effector and regulatory T cells. J Immunol　172：3157-3166，2004

regulatory T cells control the severity of viral immunoinflammatory lesions. J Immunol　172：4123-4132，2004

regulatory T cells control Leishmania major persistence and immunity. Nature　420：502-507，2002

regulatory T cells. Nat Med　10：29-30，2004

85) Scott-Browne JP, Shafiani S, Tucker-Heard G, et al : Expansion and function of Foxp3-expressing T regulatory cells during tuberculosis. J Exp Med　204：2159-2169，2007

HIV-specific T cell immune responses in vitro and are associated with favorable clinical markers of disease status. J Exp Med　200：331-343，2004

87) Pereira LE, Villinger F, Onlamoon N, et al : Simian immunodeficiency virus (SIV) infection influences the level and function of regulatory T cells in SIV-infected rhesus macaques but not SIV-infected sooty mangabeys. J Virol　81：4445-4456，2007

T cell response in HCV-infected patients with normal versus abnormal alanine aminotransferase levels. Clin Exp Immunol　144：188-196，2006

89) Bates GJ, Fox SB, Han C, et al : Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol　24：5373-5380，2006

90) Curiel TJ, Morris C, Brumlik M, et al : Peptides identified through phage display direct immunogenic antigen to dendritic cells. J Immunol　172：7425-7431，2004

regulatory T cells affect the development and progression of hepatocarcinogenesis. Clin Cancer Res　13：902-911，2007

92) Wolf D, Wolf AM, Rumpold H, et al : The expression of the regulatory T cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer. Clin Cancer Res　11：8326-8331，2005

93) Onizuka S, Tawara I, Shimizu J, et al : Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor α) monoclonal antibody. Cancer Res　59：3128-3133，1999

T cells : a common basis between tumor immunity and autoimmunity. J Immunol　163：5211-5218，1999

95) Kullberg MC, Ward JM, Gorelick PL, et al : Helicobacter hepaticus triggers colitis in specific-pathogen-free interleukin-10 (IL-10)-deficient mice through an IL-12- and gamma interferon-dependent mechanism. Infect Immun　66：5157-5166，1998

96) Sun CM, Hall JA, Blank RB, et al : Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med　204：1775-1785，2007

97) Benson MJ, Pino-Lagos K, Rosemblatt M, et al : All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med　204：1765-1774，2007

regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J Exp Med　204：1757-1764，2007

99) Mucida D, Park Y, Kim G, et al : Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science　317：256-260，2007