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 4

IL-4 and IL-10 are expressed by TIM-1+ B cells and induced by TIM-1 ligation.

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IL-4 and IL-10 are expressed by TIM-1+ B cells and induced by TIM-1 liga...
Splenic CD19+ B cells from BALB/c mice were naive, transplanted with B6 islets, or transplanted and treated with anti–TIM-1 or control Ig on day 14. (A) IL-4 and IL-10 expression, gated on CD19+ B cells (control and total B cells) or on TIM-1– and TIM-1+ B cells. IL-4 (EGFP) versus control (WT littermates); IL-10 (intracellular staining) versus control (isotype). (B) Frequency (mean + SD) of B cells expressing cytokines from mice in A. *P < 0.05 vs. naive; #P < 0.05 vs. all other groups. (C) Frequency (mean + SD) of cytokine expression on TIM-1– versus TIM-1+ B cells from anti–TIM-1–treated allograft recipients. *P < 0.01 vs. TIM-1–. (D) TIM-1 expression (mean + SD) on B, CD4+ T, and CD8+ T cells. *P < 0.05 vs. naive; #P < 0.05 vs. all other groups. (E) Total number (mean + SD) of splenic B and CD4+ T cells. (A–E) n ≥ 5 mice/group in at least 3 experiments. (F and G) Sorted TIM-1– “index” B cells (see Methods) from naive BALB/c mice were transferred into syngeneic JHD (F) or RAG2-KO (G) mice. Recipients were naive or were exposed to alloantigen (allograft or allogeneic splenocytes) with or without anti–TIM-1 or control Ig. TIM-1 expression on index B cells recovered from spleen (day 14) is shown in representative dot plots (F), or as frequency (G; mean + SD). n = 3 mice/group. *P < 0.05 vs. no allograft; #P < 0.01 vs. all other groups. Numbers denote percent cells in the respective quadrants.