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

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 7

TIM-1+ B cells are highly enriched for IL-10 expression across a wide spectrum of phenotypes.

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TIM-1+ B cells are highly enriched for IL-10 expression across a wide sp...
BALB/c splenocytes were assessed for expression of various cell surface markers and IL-10 by multicolor flow cytometry. n = 3–6 mice/group in at least 3 independent experiments. (A) Left: Representative expression of CD5 versus CD1d on CD19+ B cells in naive mice with the CD1dhiCD5+ population (2.3% of total B cells; rectangular gate). Right: IL-10 and TIM-1 expression on CD19+ (total B) and on TIM-1+ and TIM-1– B cells within the CD1dhiCD5+ and non-CD1dhiCD5+ B cell populations. (B) Representative expression of markers on CD19+IL-10+ B cells. Cells within the IL-10+ B cell gate were assessed for CD1d and CD5 or TIM-1 expression. (C) Percent (mean + SD) B cells expressing TIM-1 within FO, MZ, T2-MZ, T1, CD1dhiCD5+, and B1 B cells from naive and transplanted mice with or without anti–TIM-1 or control Ig treatment. *P < 0.05 vs. naive; #P < 0.05 vs. other allograft recipients. (D) IL-10 expression (mean + SD) on B cell subpopulations and mice as in C. *P < 0.05 vs. other total B cell groups; #P < 0.05 vs. other TIM-1+ B cell groups. P < 0.05, TIM-1+ vs. TIM-1– (all groups). Numbers denote percent cells within the designated areas.