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Immunostimulatory Tim-1–specific antibody deprograms Tregs and prevents transplant tolerance in mice

2008; American Society for Clinical Investigation; Volume: 118; Issue: 2 Linguagem: Inglês

10.1172/jci32562

1558-8238

Nicolas Degauque, Christophe Mariat, James J. Kenny, Dong Zhang, Wenda Gao, Minh Diem Vu, Sophoclis P. Alexopoulos, Mohammed Oukka, Dale T. Umetsu, Rosemarie H. DeKruyff, Vijay K. Kuchroo, Xin Xiao Zheng, Terry B. Strom,

Immune Cell Function and Interaction

T cell Ig mucin (Tim) molecules modulate CD4+ T cell responses. In keeping with the view that Tim-1 generates a stimulatory signal for CD4+ T cell activation, we hypothesized that an agonist Tim-1–specific mAb would intensify the CD4+ T cell–dependant allograft response. Unexpectedly, we determined that a particular Tim-1–specific mAb exerted reciprocal effects upon the commitment of alloactivated T cells to regulatory and effector phenotypes. Commitment to the Th1 and Th17 phenotypes was fostered, whereas commitment to the Treg phenotype was hindered. Moreover, ligation of Tim-1 in vitro effectively deprogrammed Tregs and thus produced Tregs unable to control T cell responses. Overall, the effects of the agonist Tim-1–specific mAb on the allograft response stemmed from enhanced expansion and survival of T effector cells; a capacity to deprogram natural Tregs; and inhibition of the conversion of naive CD4+ T cells into Tregs. The reciprocal effects of agonist Tim-1–specific mAbs upon effector T cells and Tregs serve to prevent allogeneic transplant tolerance.