Immunostimulatory Tim-1–specific antibody deprograms Tregs and prevents transplant tolerance in mice
Nicolas Degauque, … , Xin Xiao Zheng, Terry B. Strom
Nicolas Degauque, … , Xin Xiao Zheng, Terry B. Strom
Published December 13, 2007
Citation Information: J Clin Invest. 2008;118(2):735-741. https://doi.org/10.1172/JCI32562.
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Research Article

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

Abstract

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.

Authors

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

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Figure 3

3B3 anti–Tim-1 mAb prevents the de novo induction of Foxp3+ Tregs from Teffs and promotes the differentiation of Th17 cells.

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3B3 anti–Tim-1 mAb prevents the de novo induction of Foxp3+ Tregs from T...
CD4+GFP(Foxp3)– T cells isolated from naive C57BL/6 Foxp3-GFP knock-in mice were cultured with highly mature syngeneic DCs plus anti-CD3 mAb in the presence of IgG2a mAb or anti–Tim-1 mAb and in the presence or absence of TGF-β. Induction of Foxp3 expression was assessed 3 days later by quantitative real-time PCR (A) or by intracellular staining of Foxp3 (B). Quantification of conversion of CD4+GFP(Foxp3)– to CD4+Foxp3+ Tregs at the level of protein expression was determined by gating onto the CD4+ fraction. Differentiation of Th17 cells was assessed by intracellular staining of IL-17 and quantified at the level of protein expression by gating onto the CD4+ fraction. Data are presented as the mean ± SEM of 3 independent experiments (A) or are representative of 3 independent experiments (B).