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The author(s) declarefinancial support was received for theresearch, authorship, and/or publication of this article. This workwas supported in part by Genome Canada and Genome Alberta (GAPP program), the Canadian Institutes of Health Research (CIHR) (FDN-353029, PJT-479040, PJT-479038, FRN-168480 (with JDRF), DT4-179512), the European Union (HORIZON-HLTH-2022,project 101076383-PHOENIX-), Ministerio de Ciencia e Innovacion of Spain (MCIN; PID2021-125493OB-I00), Generalitatde Catalunya (SGR and CERCA Programmes) and Red Espanola de Supercomputacion (RES, providing CSUC resources). JM, JG and PS were supported by predoctoral studentship from FPU (MINECO). PS e was an investigator of the Ramon y Cajal reintegration program and was supported by a JDRF Career Development Award.

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Transcriptional re-programming of liver-resident iNKT cells into T-regulatory type-1-like liver iNKT cells involves extensive gene de-methylation

Publicat a:Frontiers In Immunology. 15 1454314- - 2024-09-09 15(), DOI: 10.3389/fimmu.2024.1454314

Autors: Montaño, J; Garnica, J; Moro, J; Solé, P; Serra, P; Santamaria, P; Yamanouchi, J; Mondal, D; Yang, Y

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Unlike conventional CD4+ T cells, which are phenotypically and functionally plastic, invariant NKT (iNKT) cells generally exist in a terminally differentiated state. Na & iuml;ve CD4+ T cells can acquire alternative epigenetic states in response to different cues, but it remains unclear whether peripheral iNKT cells are epigenetically stable or malleable. Repetitive encounters of liver-resident iNKT cells (LiNKTs) with alpha-galactosylceramide (alpha GalCer)/CD1d-coated nanoparticles (NPs) can trigger their differentiation into a LiNKT cell subset expressing a T regulatory type 1 (TR1)-like (LiNKTR1) transcriptional signature. Here we dissect the epigenetic underpinnings of the LiNKT-LiNKTR1 conversion as compared to those underlying the peptide-major histocompatibility complex (pMHC)-NP-induced T-follicular helper (TFH)-to-TR1 transdifferentiation process. We show that gene upregulation during the LINKT-to-LiNKTR1 cell conversion is associated with demethylation of gene bodies, inter-genic regions, promoters and distal gene regulatory elements, in the absence of major changes in chromatin exposure or deposition of expression-promoting histone marks. In contrast, the na & iuml;ve CD4+ T cell-to-TFH differentiation process involves extensive remodeling of the chromatin and the acquisition of a broad repertoire of epigenetic modifications that are then largely inherited by TFH cell-derived TR1 cell progeny. These observations indicate that LiNKT cells are epigenetically malleable and particularly susceptible to gene de-methylation.

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