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Cited by 462T-cell and B-cell ImmunologyImmunotherapy and Immune ResponsesImmune Response and Inflammation

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

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Ding, Qing, Yeung, Melissa, Camirand, Geoffrey, Zeng, Qiang, Akiba, Hisaya, Yagita, Hideo, Chalasani, Geetha, Sayegh, Mohamed H. +2 more·2011·Journal of Clinical Investigation
DOI 10.1172/jci46274PMC PMC3163958
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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 CD1d(hi)CD5+. 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.

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  • Bregs are B cells with regulatory and immunosuppressive functions that maintain immunological homeostasis by producing IL-10, IL-35, and TGFβ, thereby suppressing immunopathology.

    “Bregs is a generic term used to define B cells endowed with regulatory and immunosuppressive functions. They play a crucial role in maintain­ ing immunological homeostasis by producing anti-inflammatory cyto­ kines such as interleukin-10 (IL-10), IL-35, and transforming growth factor-beta (TGFβ ), thereby suppressing immunopathology.”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [56]

    The Introduction describes regulatory B cells that inhibit inflammation in an IL-10-dependent manner, and the Discussion says Bregs promote tolerance in several mouse models. These passages support the regulatory function and IL-10 portion of the claim, but the paper does not identify IL-35 or TGFβ as cytokines produced by Bregs. Page numbers are unavailable in our copy. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Bregs inhibit the expansion of pathogenic T cells and other pro-inflammatory immune cells, thereby preventing excessive immune activation.

    “Bregs inhibit the expansion of pathogenic T cells and other pro-inflammatory immune cells, thereby preventing excessive immune activation [55 -58].”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [56]

    The allograft-results section (page not provided) reports that transferred TIM-1+ Bregs inhibited IFN-γ expression by endogenous CD4+ T cells, and the Discussion reports Breg-mediated allograft tolerance in mice. Those passages support regulation of inflammatory T-cell responses, but they do not show inhibited expansion of pathogenic T cells or other pro-inflammatory immune cells. (LLM, conf=0.86)

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Authors
Ding, Q., Yeung, M., Camirand, G., Zeng, Q., Akiba, H., Yagita, H., Chalasani, G., Sayegh, M. H., Najafian, N., & Rothstein, D. M.
Affiliations
  • University of Pittsburgh (US)
  • Brigham and Women's Hospital (US)
  • Juntendo University (JP)
Corresponding author
Rothstein, David M.
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2011-09-01
Volume
121
Issue
9
Pages
3645-3656
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci46274
PMC
PMC3163958
OpenAlex
W2001101603
Cited by
462
References
1
Citations by year
2026: 14 · 2025: 23 · 2024: 21 · 2023: 17 · 2022: 23 · 2021: 32 · 2020: 34 · 2019: 39 · 2018: 32 · 2017: 32 · 2016: 36 · 2015: 44 · 2014: 52 · 2013: 33 · 2012: 22
FWCI
16.32
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • Japan Society for the Promotion of Science (22591098)
  • National Institute of Allergy and Infectious Diseases (R01AI097361, AI070820, R01AI070820, R01AI079177)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
regulatory B cells, TIM-1, IL-10, allograft tolerance, IL-4 signaling, Th2 immune response, transitional B cells, marginal zone B cells, follicular B cells, costimulatory molecules, immune tolerance
MeSH terms
Hepatitis A Virus Cellular Receptor 1, Animals, Autoimmune Diseases, B-Lymphocytes, DNA-Binding Proteins, Humans, Immune Tolerance, Membrane Proteins, Mice, Inbred BALB C, Mice, Inbred C57BL, T-Lymphocytes, Signal Transduction, Antigens, CD, Interleukin-4, Lymphocyte Subsets, Cytokines, Interleukin-10, Mice, Knockout, Transplantation Tolerance, Mice

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