Deficiency of CBL and CBLB ubiquitin ligases leads to hyper T follicular helper cell responses and lupus by reducing BCL6 degradation.

Autor:	Li X; Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China; Montreal Clinical Research Institute, Montreal, QC H2W 1R7, Canada; Division of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada. Electronic address: lixinfb@gmail.com., Sun W; Montreal Clinical Research Institute, Montreal, QC H2W 1R7, Canada; Division of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada., Huang M; Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China., Gong L; Montreal Clinical Research Institute, Montreal, QC H2W 1R7, Canada; Division of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada., Zhang X; Montreal Clinical Research Institute, Montreal, QC H2W 1R7, Canada; Department of Microbiology, Infectiology, and Immunology, University of Montreal, Montreal, QC H3T 1J4, Canada., Zhong L; Montreal Clinical Research Institute, Montreal, QC H2W 1R7, Canada; Division of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada., Calderon V; Montreal Clinical Research Institute, Montreal, QC H2W 1R7, Canada., Bian Z; School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong 511442, China., He Y; Department of Rheumatology and Immunology, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China., Suh WK; Montreal Clinical Research Institute, Montreal, QC H2W 1R7, Canada; Division of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada., Li Y; Department of Rheumatology and Immunology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China., Song T; The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA., Zou Y; The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA., Lian ZX; Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China. Electronic address: zxlian@gdph.org.cn., Gu H; Montreal Clinical Research Institute, Montreal, QC H2W 1R7, Canada; Division of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada; Department of Microbiology, Infectiology, and Immunology, University of Montreal, Montreal, QC H3T 1J4, Canada. Electronic address: hua.gu@ircm.qc.ca.
Jazyk:	angličtina
Zdroj:	Immunity [Immunity] 2024 Jul 09; Vol. 57 (7), pp. 1603-1617.e7. Date of Electronic Publication: 2024 May 17.
DOI:	10.1016/j.immuni.2024.04.023
Abstrakt:	Recent evidence reveals hyper T follicular helper (Tfh) cell responses in systemic lupus erythematosus (SLE); however, molecular mechanisms responsible for hyper Tfh cell responses and whether they cause SLE are unclear. We found that SLE patients downregulated both ubiquitin ligases, casitas B-lineage lymphoma (CBL) and CBLB (CBLs), in CD4 + T cells. T cell-specific CBLs-deficient mice developed hyper Tfh cell responses and SLE, whereas blockade of Tfh cell development in the mutant mice was sufficient to prevent SLE. ICOS was upregulated in SLE Tfh cells, whose signaling increased BCL6 by attenuating BCL6 degradation via chaperone-mediated autophagy (CMA). Conversely, CBLs restrained BCL6 expression by ubiquitinating ICOS. Blockade of BCL6 degradation was sufficient to enhance Tfh cell responses. Thus, the compromised expression of CBLs is a prevalent risk trait shared by SLE patients and causative to hyper Tfh cell responses and SLE. The ICOS-CBLs axis may be a target to treat SLE. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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