| Autor: |
Ruihan Tang, Nandini Acharya, Ayshwarya Subramanian, Vinee Purohit, Marcin Tabaka, Yu Hou, Danyang He, Karen O. Dixon, Connor Lambden, Junrong Xia, Orit Rozenblatt-Rosen, Raymond A. Sobel, Chao Wang, Aviv Regev, Ana C. Anderson, Vijay K. Kuchroo |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Sci Immunol |
| ISSN: |
2470-9468 |
| Popis: |
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 TH1, TH17 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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