CD154 is a negative regulator of autoaggressive CD8+ T cells in type 1 diabetes.
TNF/CD80 mice, a CD8(+) T cell-mediated model for type 1 diabetes, transgenically express tumor necrosis factor alpha (TNF-alpha) and the costimulatory molecule CD80 in their pancreatic islets. Here we show that these molecules bypass the need for CD40-CD154 costimulatory interactions in activation of CD8(+) T cells, allowing us to determine the role of CD40-CD154 signals in regulation of autoaggressive CD8(+) T cells after their in vivo priming. TNF/CD80 CD154-deficient mice rapidly develop diabetes, whereas CD154-sufficient mice do not. This finding correlates with the decreased numbers of CD4(+)CD25(+) T regulatory (T(R)) cells in the islets and pancreatic lymph nodes, in comparison to disease-protected CD154-sufficient mice. Administration of a CD40 agonistic antibody induces a systemic and tissue-specific increase in T(R) cells. However, this increase fails to delay diabetes development in the absence of CD154. Adoptive transfer studies show that CD8(+) T cells from TNF/CD80 CD154-deficient, but not CD154-sufficient, mice are resistant to regulation in vivo. This study provides evidence that CD40-transduced signals initiate T(R) cell increase in vivo and that CD154-transduced signals sensitize autoaggressive CD8(+) T cells to suppression.
McGregor
Catrin M
CM
Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, Cambridge University, Cambridge CB2 2XY, United Kingdom.
Schoenberger
Stephen P
SP
Green
E Allison
EA
D000818:Animals; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000235:genetics* / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007515:Islets of Langerhans / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics
D019013:CD40 Antigens; D012333:RNA, Messenger; D023201:CD40 Ligand