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 6

TIM-1+ B cells prolong allograft survival in a donor-specific and IL-10–dependent manner.

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TIM-1+ B cells prolong allograft survival in a donor-specific and IL-10–...
(A) WT, Il4ra–/–, or Il10–/– BALB/c recipients of B6 islets were treated with anti–TIM-1. On day 14, splenic TIM-1+ and TIM-1– B cells were sort-purified and transferred (107) into otherwise-untreated JHD recipients of islet allografts from the same (B6) strain. Shown are Kaplan-Meir plots of graft survival. #P < 0.01 vs. all other groups; *P < 0.05 vs. untreated. (B) TIM-1+ B cells from spleen of naive BALB/c mice or from untreated BALB/c recipients of B6 or C3H islet allografts (day 14) were sort-purified and transferred (107) into JHD recipients of B6 islets without further treatment. Shown are Kaplan-Meir plots of graft survival. #P < 0.01 vs. other groups. (C) JHD IL-4 EGFP (JHD×4get) recipients of B6 islets were untreated or received 107 TIM-1+ or TIM-1– B cells from anti–TIM-1–treated BALB/c allograft recipients as in A. Shown is representative IL-4 (EGFP) or IFN-γ, IL-10, and Foxp3 (intracellular staining) expression by flow cytometry on splenic CD4+ T cells from recipients 14 days after receiving TIM-1+, TIM-1–, or no B cells. Numbers denote percent CD4+ T cells expressing IL-4, IFN-γ, IL-10, or Foxp3. n = 3 mice/group.