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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

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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 1

Effect of anti–Tim-1 mAb on alloreactive CD4+ and CD8+ Teff responses in vitro.

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Effect of anti–Tim-1 mAb on alloreactive CD4+ and CD8+ Teff responses in...
CFSE-labeled C57BL/6 CD4+CD25– and CD8+CD25– cells were stimulated with highly mature allogeneic DBA/2 DCs in the presence of anti–Tim-1 mAb or IgG2a isotype control mAb. Analysis of the CFSE profile (A) and enumeration of the absolute number of CD3+CD4+ or CD8+ cells (B) were used to assess the proliferation and expansion of alloreactive T cells after 2 (A) and 4 (A and B) days of culture. (C) The effect of anti–Tim-1 mAb on the proportion of cells programmed for apoptosis (annexin V+ cells) in the proliferating cell population was assessed after 4 days of culture. (D) To gain further insight, we analyzed Bcl-2 transcript expression in alloreactive CD4+ or CD8+ cells after 2 days of culture. (E) Finally, secretion of IFN-γ (Th1) and IL-17 (Th17) by alloreactive Teffs after 4 days of culture was assessed by intracellular staining. Data represent 1 of 8 independent experiments (A and E) or are presented as the mean ± SEM of at least 5 independent experiments (B–D).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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