PMID- 35275752 OWN - NLM STAT- MEDLINE DCOM- 20220503 LR - 20231014 IS - 2470-9468 (Electronic) IS - 2470-9468 (Linking) VI - 7 IP - 69 DP - 2022 Mar 11 TI - Tim-3 adapter protein Bat3 acts as an endogenous regulator of tolerogenic dendritic cell function. PG - eabm0631 LID - 10.1126/sciimmunol.abm0631 [doi] AB - Dendritic cells (DCs) sense environmental cues and adopt either an immune-stimulatory or regulatory phenotype, thereby fine-tuning immune responses. Identifying endogenous regulators that determine DC function can thus inform the development of therapeutic strategies for modulating the immune response in different disease contexts. Tim-3 plays an important role in regulating immune responses by inhibiting the activation status and the T cell priming ability of DC in the setting of cancer. Bat3 is an adaptor protein that binds to the tail of Tim-3; therefore, we studied its role in regulating the functional status of DCs. In murine models of autoimmunity (experimental autoimmune encephalomyelitis) and cancer (MC38-OVA-implanted tumor), lack of Bat3 expression in DCs alters the T cell compartment-it decreases T(H)1, T(H)17 and cytotoxic effector cells, increases regulatory T cells, and exhausted CD8(+) tumor-infiltrating lymphocytes, resulting in the attenuation of autoimmunity and acceleration of tumor growth. We found that Bat3 expression levels were differentially regulated by activating versus inhibitory stimuli in DCs, indicating a role for Bat3 in the functional calibration of DC phenotypes. Mechanistically, loss of Bat3 in DCs led to hyperactive unfolded protein response and redirected acetyl-coenzyme A to increase cell intrinsic steroidogenesis. The enhanced steroidogenesis in Bat3-deficient DC suppressed T cell response in a paracrine manner. Our findings identified Bat3 as an endogenous regulator of DC function, which has implications for DC-based immunotherapies. FAU - Tang, Ruihan AU - Tang R AD - Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. AD - Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Acharya, Nandini AU - Acharya N AD - Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. AD - Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Subramanian, Ayshwarya AU - Subramanian A AD - Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. AD - Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. AD - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. FAU - Purohit, Vinee AU - Purohit V AUID- ORCID: 0000-0001-8093-5540 AD - Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. AD - Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Tabaka, Marcin AU - Tabaka M AUID- ORCID: 0000-0002-6166-2820 AD - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. FAU - Hou, Yu AU - Hou Y AUID- ORCID: 0000-0001-7875-7087 AD - Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. AD - Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. FAU - He, Danyang AU - He D AUID- ORCID: 0000-0002-3613-4188 AD - Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. AD - Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Dixon, Karen O AU - Dixon KO AUID- ORCID: 0000-0001-7811-5439 AD - Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. AD - Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Lambden, Connor AU - Lambden C AD - Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. AD - Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Xia, Junrong AU - Xia J AUID- ORCID: 0000-0002-2818-1494 AD - Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. AD - Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Rozenblatt-Rosen, Orit AU - Rozenblatt-Rosen O AUID- ORCID: 0000-0001-6313-3570 AD - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. FAU - Sobel, Raymond A AU - Sobel RA AUID- ORCID: 0000-0002-0477-9002 AD - Department of Pathology, Stanford University, Stanford, CA, USA. FAU - Wang, Chao AU - Wang C AUID- ORCID: 0000-0003-3084-6093 AD - Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. AD - Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Regev, Aviv AU - Regev A AUID- ORCID: 0000-0003-3293-3158 AD - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. AD - Department of Biology, Howard Hughes Medical Institute and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. FAU - Anderson, Ana C AU - Anderson AC AUID- ORCID: 0000-0002-0877-2932 AD - Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. AD - Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Kuchroo, Vijay K AU - Kuchroo VK AUID- ORCID: 0000-0001-7177-2110 AD - Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. AD - Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. AD - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. LA - eng GR - P01 AI056299/AI/NIAID NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - R01 CA229400/CA/NCI NIH HHS/United States GR - P01 AI039671/AI/NIAID NIH HHS/United States GR - U19 AI133524/AI/NIAID NIH HHS/United States GR - R01 AI144166/AI/NIAID NIH HHS/United States GR - P01 AI073748/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20220311 PL - United States TA - Sci Immunol JT - Science immunology JID - 101688624 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Bag6 protein, mouse) RN - 0 (Hepatitis A Virus Cellular Receptor 2) RN - 0 (Molecular Chaperones) RN - 0 (Nuclear Proteins) SB - IM MH - Adaptor Proteins, Signal Transducing MH - Animals MH - Autoimmunity MH - Dendritic Cells MH - *Encephalomyelitis, Autoimmune, Experimental MH - *Hepatitis A Virus Cellular Receptor 2 MH - Mice MH - Molecular Chaperones/*metabolism MH - Nuclear Proteins/*metabolism MH - T-Lymphocytes, Regulatory PMC - PMC9273260 MID - NIHMS1804543 COIS- Competing interests: All other authors declare that they have no competing interests. EDAT- 2022/03/12 06:00 MHDA- 2022/05/04 06:00 PMCR- 2023/03/11 CRDT- 2022/03/11 17:10 PHST- 2022/03/11 17:10 [entrez] PHST- 2022/03/12 06:00 [pubmed] PHST- 2022/05/04 06:00 [medline] PHST- 2023/03/11 00:00 [pmc-release] AID - 10.1126/sciimmunol.abm0631 [doi] PST - ppublish SO - Sci Immunol. 2022 Mar 11;7(69):eabm0631. doi: 10.1126/sciimmunol.abm0631. Epub 2022 Mar 11.