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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 Article has an altmetric score of 3

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 2

Effect of 3B3 anti–Tim-1 mAb on alloreactive Tregs in vitro.

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Effect of 3B3 anti–Tim-1 mAb on alloreactive Tregs in vitro.
(A) CFSE-la...
(A) CFSE-labeled CD4+CD25+ Tregs were stimulated with mature allogeneic DCs in the presence of anti–Tim-1 mAb or IgG2a isotype control mAb. Proliferation of alloreactive CD4+CD25+ Tregs was assessed by flow cytometry after 6 days of culture through analysis of the CFSE profile of CD4+ T cells. (B) Next, proliferating CFSEdim CD4+CD25+ Tregs were isolated by flow cytometry for RNA extraction, and relative expression of Treg-associated transcripts was determined by quantitative real-time PCR. (C) FACS-sorted GFP(Foxp3)+ Tregs from Foxp3-GFP knock-in mice were cocultured with mature allogeneic DCs in the presence of anti–Tim-1 mAb or IgG2a isotype control mAb. Foxp3 gene expression was assessed by quantitative real-time PCR on days 2, 4 and 6. (D) Neutralizing anti–IL-6 mAb or isotype control mAb was added to the culture of GFP(Foxp3)+ Tregs with mature allogeneic DCs. After 6 days of culture, Foxp3 expression was analyzed by quantitative real-time PCR. (E) CFSE-labeled CD45.1+ Teffs (CD4+CD25–) were stimulated by plate-bound anti-CD3 and soluble anti-CD28 mAb for 4 days (Teff alone), or cocultured with alloreactive CD45.2+ Tregs, previously stimulated either in the presence of IgG2a isotype control mAb (Isotype control mAb proliferating Treg/Teff) or in the presence of anti–Tim-1 mAb (Anti-Tim 1 mAb proliferating Treg/Teff). Proliferation of Teffs was assessed by flow cytometry, based on the CFSE profile of CD45.1+ cells. Data are representative of 4 (A and E) independent experiments or are presented as the mean ± SEM of 4 different independent experiments (B–D).

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

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