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 1

B lymphocytes express relatively high levels of TIM-1.

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B lymphocytes express relatively high levels of TIM-1. (A) Representativ...
(A) Representative flow cytometry plots showing TIM-1 expression on splenic CD4+ and CD8+ T cells and CD19+ B cells in naive BALB/c mice or at 14 days after immunization with either allogeneic (B6) islet transplantation (Txpl) or OVA (20 μg with 4 mg alum i.p. on days 0 and 7). Cell staining was performed in the presence of anti-CD16/CD32 to block FcR binding, and isotype- and fluorochrome-matched negative controls were used to set the cursors. Isotype control staining for CD19+ cells is shown at right. n ≥ 3 per group. (B) Representative flow cytometry plots showing TIM-1 expression on CD19+ B cells from naive mice assessed by indirect staining with anti–TIM-1 mAbs RMT1-10, RMT1-4, and 3B3 followed by PE-conjugated anti-rat Ig secondary mAb. n = 3 per group. (C) Anti–TIM-1 immunoblot of cell lysates from sort-purified T cells, B cells, TIM-1+ B cells, and TIM-1– B cells. Representative of 2 independent experiments. Numbers denote percent TIM-1+ cells within each population.