Bat3 promotes T cell responses and autoimmunity by repressing Tim-3-mediated cell death and exhaustion
Open accessAbstract
T cell immunoglobulin and mucin domain–containing 3 (Tim-3) is an inhibitory receptor that is expressed on exhausted T cells during infection with HIV-1 and hepatitis C virus. By contrast, Tim-3 expression and function are defective in multiple human autoimmune diseases. However, the molecular mechanisms modulating Tim-3 function are not well understood. Here we show that human leukocyte antigen B (HLA-B)-associated transcript 3 (Bat3) binds to, and represses the function of, Tim-3. Bat3 protects T helper type 1 (TH1) cells from galectin-9–mediated cell death and promotes both proliferation and proinflammatory cytokine production. Bat3-deficient T cells have elevated expression of exhaustion-associated molecules such as Tim-3, Lag3, Prdm1 and Pbx3, and Bat3 knockdown in myelin-antigen–specific CD4+ T cells markedly inhibits the development of experimental autoimmune encephalomyelitis while promoting the expansion of a dysfunctional Tim-3hi, interferon-γ (IFN-γ)loCD4+ cell population. Furthermore, expression of Bat3 is reduced in exhausted Tim-3+ T cells from mouse tumors and HIV-1–infected individuals. These data indicate that Bat3 acts as an inhibitor of Tim-3–dependent exhaustion and cell death. Bat3 may thus represent a viable therapeutic target in autoimmune disorders, chronic infections and cancers.
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Bat3 localization at the Tim-3 cytoplasmic tail allows continued T cell proliferation and IFNγ production, an effect lost in Bat3-deficient cells and upon Tim-3 binding to galectin-9.
“Bat3 localization at this protein region allows T cells continued proliferation and IFNγ production, an effect that was lost on Bat3 deficient cells and upon Tim-3 binding to galectin-9.”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [66]
Bat3 modulates Tim-3 function on T cells by interacting with the Tim-3 cytoplasmic tail.
“it has been postulated that the human leukocyte antigen (HLA)-B-associated transcript 3 (Bat3) modulates Tim-3 function on T cells by interacting with Tim-3 cytoplasmic tail [66].”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [66]
Release of BAT3 suggests that FYN tyrosine-protein kinase links with the TIM-3 cytoplasmic tail to generate inhibitory signaling that causes anergy of T cells by activating PAG1, prompting recruitment of CSK, leading to phosphorylating LCK and suppressing T cells.
“Release of BAT3 suggests that FYN tyrosine‐protein kinase links with the TIM‐3 cytoplasmic tail to generate inhibitory signaling that causes anergy of T cells by activating the transmembrane protein phosphoprotein membrane anchor with glycosphingolipid microdomains 1 (PAG1). This prompts the recruitment of tyrosine kinase (CSK), leading to phosphorylating LCK and suppressing T cells [308, 312].”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [308]
Tyrosine kinase FYN and human leukocyte antigen B (HLA-B)-associated transcript 3 (BAT3) were suggested to inhibit the cytoplasmic tail of TIM-3 signaling.
“Nevertheless, tyrosine kinase FYN and human leukocyte antigen B (HLA‐B)‐associated transcript 3 (BAT3) were suggested to inhibit the cytoplasmic tail of TIM‐3 signaling [307, 308, 309].”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [308]
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Self-citation
- Authors
- Rangachari, M., Zhu, C., Sakuishi, K., Xiao, S., Karman, J., Chen, A., Angin, M., Wakeham, A., Greenfield, E. A., Sobel, R. A., Okada, H., McKinnon, P. J., Mak, T. W., Addo, M. M., Anderson, A. C., & Kuchroo, V. K.
- Affiliations
- Brigham and Women's Hospital (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- Princess Margaret Cancer Centre (CA)
- Dana-Farber Cancer Institute (US)
- Stanford Medicine (US)
- University of Toronto (CA)
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Kuchroo, Vijay K
- ORCID
- Venue
- Nature Medicine
- Published
- 2012-08-05
- Volume
- 18
- Issue
- 9
- Pages
- 1394-1400
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC3491118
- OpenAlex
- W1968791512
- Cited by
- 394
- References
- 51
- Citations by year
- 2026: 20 · 2025: 43 · 2024: 33 · 2023: 33 · 2022: 26 · 2021: 48 · 2020: 40 · 2019: 31 · 2018: 23 · 2017: 26 · 2016: 10 · 2015: 21 · 2014: 18 · 2013: 20 · 2012: 2
- FWCI
- 8.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- Funders
- Canadian Institutes of Health Research
- National Institute of Allergy and Infectious Diseases (K08AI074405, P01AI073748, AI073748, P30AI060354)
- National Institute of Diabetes and Digestive and Kidney Diseases (K01DK090105)
- National Institute of Neurological Disorders and Stroke (R01NS030843, NS038037, NS045937, P01NS038037, R01NS037956, R01NS045937)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Keywords
- BAT3, TIM-3, T cell exhaustion, galectin-9, T cell death, Th1 cells, experimental autoimmune encephalomyelitis, autoimmunity, CD4+ T cells, LAG-3, Blimp-1, PBX3, interferon-gamma, chronic viral infection, cancer immunotherapy, therapeutic target
- MeSH terms
- Hepatitis A Virus Cellular Receptor 2, Animals, DNA-Binding Proteins, Flow Cytometry, Genetic Vectors, Humans, Membrane Proteins, Retroviridae, T-Lymphocytes, Transcription Factors, Transduction, Genetic, Autoimmunity, Cell Death, Mice, Knockout, Homeodomain Proteins, Statistics, Nonparametric, Molecular Chaperones, Mice, HEK293 Cells, Real-Time Polymerase Chain Reaction
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Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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