The role of CD28 and CTLA4 in the function and homeostasis of CD4+CD25+ regulatory T cells.
CD4+CD25+ T cells regulate a variety of autoimmune and alloimmune responses including the development of autoimmune diabetes in non-obese diabetic (NOD) mice. We have examined the role of CD28/CTLA4/B7 interactions in the expansion and survival of CD4+CD25+ regulatory T cells (T(reg)) in this setting. CD28/ B7 interactions are essential in the development of T(reg) in the thymus and for their survival in the periphery. The CD28-mediated homeostasis of these cells is independent of Il2, OX40, CD40L, and survival factor Bcl-XI. In addition, analysis of T(reg) from CTLA4-deficient mice suggests that CTLA4 expression is not required for their development or function. However, non-activating anti-CTLA4 antibodies blocked the suppressor activity of regulatory cells in vitro. Thus, clinical application of co-stimulatory blockade using agents such as CTLA4Ig in the treatment of autoimmune disease may result in complicated outcomes.
Boden
Elisa
E
UCSF Diabetes Center, University of California, San Francisco, 513 Parnassus Avenue, Box 0540, HSW Room 1114, San Francisco, CA 94143-0540, USA.
Tang
Qizhi
Q
Bour-Jordan
Helene
H
Bluestone
Jeffrey A
JA
D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology*; D060908:CTLA-4 Antigen; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology; D017353:Gene Deletion; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D015375:Receptors, Interleukin-2