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

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

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 8

Model of TIM-1+IL-10+ Breg induction.

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Model of TIM-1+IL-10+ Breg induction. TIM-1+ B cells account for mos...
TIM-1+ B cells account for most IL-4+ and IL-10+ B cells, and both cytokines and TIM-1 itself can be induced by anti–TIM-1 in the face of BCR ligation. B cell IL-4 is required to promote IL-4 expression by Th2 cells in the allograft setting. IL-4 receptor signaling in B cells is essential both for TIM-1 expression and for IL-10 production by B cells. IL-4 can be derived from either B cells themselves or from Th2 cells. IL-10 expression is required for Breg activity, but not for TIM-1 expression.