title: Bat3 promotes T cell responses and autoimmunity by repressing Tim-3–mediated cell death and exhaustion.
abstract: 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.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Manu
authors.initials: M
authors.lastname: Rangachari
authors.forename: Chen
authors.initials: C
authors.lastname: Zhu
authors.forename: Kaori
authors.initials: K
authors.lastname: Sakuishi
authors.forename: Sheng
authors.initials: S
authors.lastname: Xiao
authors.forename: Jozsef
authors.initials: J
authors.lastname: Karman
authors.forename: Andrew
authors.initials: A
authors.lastname: Chen
authors.forename: Mathieu
authors.initials: M
authors.lastname: Angin
authors.forename: Andrew
authors.initials: A
authors.lastname: Wakeham
authors.forename: Edward A
authors.initials: EA
authors.lastname: Greenfield
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okada
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McKinnon
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Marylyn M
authors.initials: MM
authors.lastname: Addo
authors.forename: Ana C
authors.initials: AC
authors.lastname: Anderson
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D016923:Cell Death / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics; D005434:Flow Cytometry; D005822:Genetic Vectors; D057809:HEK293 Cells; D000072597:Hepatitis A Virus Cellular Receptor 2; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012190:Retroviridae; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D014161:Transduction, Genetic
chemical_list: C092009:BAG6 protein, human; C091732:BCL2-associated athanogene 1 protein; D004268:DNA-Binding Proteins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D014157:Transcription Factors; C064658:RAG-1 protein