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Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice
Qing Ding, … , Nader Najafian, David M. Rothstein
Qing Ding, … , Nader Najafian, David M. Rothstein
Published August 8, 2011
Citation Information: J Clin Invest. 2011;121(9):3645-3656. https://doi.org/10.1172/JCI46274.
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Research Article Immunology Article has an altmetric score of 7

Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice

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Abstract

T cell Ig domain and mucin domain protein 1 (TIM-1) is a costimulatory molecule that regulates immune responses by modulating CD4+ T cell effector differentiation. However, the function of TIM-1 on other immune cell populations is unknown. Here, we show that in vivo in mice, TIM-1 is predominantly expressed on B rather than T cells. Importantly, TIM-1 was expressed by a large majority of IL-10–expressing regulatory B cells in all major B cell subpopulations, including transitional, marginal zone, and follicular B cells, as well as the B cell population characterized as CD1dhiCD5+. A low-affinity TIM-1–specific antibody that normally promotes tolerance in mice, actually accelerated (T cell–mediated) immune responsiveness in the absence of B cells. TIM-1+ B cells were highly enriched for IL-4 and IL-10 expression, promoted Th2 responses, and could directly transfer allograft tolerance. Both cytokine expression and number of TIM-1+ regulatory B cells (Bregs) were induced by TIM-1–specific antibody, and this was dependent on IL-4 signaling. Thus, TIM-1 is an inclusive marker for IL-10+ Bregs that can be induced by TIM-1 ligation. These findings suggest that TIM-1 may be a novel therapeutic target for modulating the immune response and provide insight into the signals involved in the generation and induction of Bregs.

Authors

Qing Ding, Melissa Yeung, Geoffrey Camirand, Qiang Zeng, Hisaya Akiba, Hideo Yagita, Geetha Chalasani, Mohamed H. Sayegh, Nader Najafian, David M. Rothstein

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Figure 3

B lymphocytes are required for Th2-deviation induced by anti–TIM-1.

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B lymphocytes are required for Th2-deviation induced by anti–TIM-1.
IL-4...
IL-4 EGFP reporter mice (BALB/c) were untreated or subjected to B cell depletion with anti-CD20 followed by transplantation with B6 islets. Allograft recipients were either untreated or treated with anti–TIM-1 or control Ig as in Figure 2. On day 14 after transplantation, cytokine expression on splenic CD4+ T cells was examined by flow cytometry after in vitro stimulation (see Methods). IL-4 was detected by EGFP expression, and IFN-γ, IL-10, and Foxp3 were detected by intracellular staining. (A) Representative IL-4, IFN-γ, and IL-10 expression on CD4+ T cells, determined by flow cytometry. n ≥ 5 mice/group. (B) Representative Foxp3 and IL-10 expression by CD4+ T cells, determined by flow cytometry. n = 3 mice/group. (C) Frequency (mean + SD) gated on CD4+ T cells expressing IFN-γ, IL-4, or IL-10 in naive mice or allograft recipients treated as indicated. n ≥ 5 mice/group. *P < 0.05 vs. untreated or control Ig–treated allograft recipients; †P < 0.05 vs. other anti-CD20–treated allograft recipients; #P < 0.05 vs. anti–TIM-1–treated allograft recipients. Numbers denote percent of gated cells within the respective quadrants.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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