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A conserved transcriptional program for MAIT cells across mammalian evolution [Hsapiens_thymus_NKT]

ABSTRACT: Mucosal-Associated Invariant T (MAIT) cells recognize the riboflavin pathway-derived metabolite 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU) presented by the MHC-Ib molecule MR1. Both MR1 and the T cell receptor genes used by MAIT cells are under strong evolutionary pressure in mammals, suggesting an important role of 5-OP-RU-specific T cells across species. In humans and mice, MAIT cells acquire distinctive effector functions linked to the expression of the master transcription factor ZBTB16 (PLZF) during thymic development. Conservation of a unique differentiation program in 5-OP-RU-specific T cells from other species is unclear. Here, we used single-cell RNA sequencing to characterize the development of 5-OP-RU-specific T cells in 6 species spanning 110 million years of mammalian evolution. Cross-species comparative analyses revealed a conserved sequence of transcriptional events underlying the maturation of 5-OP-RU-specific thymocytes, marked by the early expression of ZBTB16 in all species. MAIT cells also co-expressed the transcription factors TBX21 (Tbet) and RORC (RORgt) in human, sheep, cattle and opossum. By contrast, Tbet and RORgt were expressed by distinct subsets of MAIT cells in the thymus of rodents, including pet mice and >30 genetically diverse mouse strains, dismissing a laboratory mouse artifact. In mice, RORgt+ MAIT cells further matured in the mesenteric lymph nodes and intestines to acquire a transcriptional program remarkably conserved in MAIT cells from non-rodent species and characterized by co-expression of type 1 and type 17 effector genes, but also genes associated with cytotoxicity and tissue repair. Thus, we define a deeply conserved transcriptional program for 5-OP-RU-specific T cells, which may help understand their functions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE239556 | GEO | 2023/12/04

REPOSITORIES: GEO

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Project description:MAIT cells are multifunctional innate-like effector cells recognizing bacterial-derived vitamin B metabolites presented by the non-polymorphic MHC class I related-1 molecule (MR1). Activated MAIT cells can exert regulatory, pro-inflammatory, or cytotoxic responses that enable the direct killing of infected cells. While tremendous progress regarding the multifaceted roles of MAIT cells has been made in the last decade, our understanding of the MR1-mediated responses of MAIT cells upon their interaction with other immune cells is still incomplete. Here, we performed the first translatome study of primary human MAIT cells interacting with THP-1 monocytes in a bicellular system. We analyzed the interaction between MAIT and THP-1 cells in the presence of the activating 5-OP-RU or the inhibitory Ac-6-FP MR1-ligand. Using bio-orthogonal non-canonical amino acid tagging (BONCAT) we were able to enrich selectively those proteins that were newly translated during MR1-dependent cellular interaction. Subsequently, newly translated proteins were measured cell-type-specifically by ultrasensitive proteomics to decipher the coinciding immune responses in both cell types. This strategy identified over 2,000 MAIT and 3,000 THP-1 active protein translations following MR-1 ligand stimulations. Translation of both cell types was more efficiently induced by 5-OP-RU in comparison to Ac-6-FP, which correlated with higher conjugation frequencies and CD3 polarization at immunological synapses. In addition to known effector responses, protein translations uncovered type I and type II Interferon-driven protein expression profiles in both 5-OP-RU-stimulated MAIT and THP-1 cells. Interestingly, the translatome of THP-1 macrophages suggested that activated MAIT cells can impact M1/M2 polarization in these cells. Indeed, gene and surface expression of CXCL10, IL-1, CD80, and CD206 confirmed an M1-like phenotype of macrophages being induced in the presence of 5-OP-RU-activated MAIT cells. Furthermore, we validated that the Interferon-driven translatome was accompanied by the induction of an antiviral phenotype in THP-1 cells, which were found able to suppress viral replication following conjugation with MR1-activated MAIT cells. In conclusion, BONCAT translatomics extended our knowledge of MAIT cell immune responses at the protein level and discovered that MR1-activated MAIT cells are sufficient to induce M1 polarization and an anti-viral program of macrophages.

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A conserved transcriptional program for MAIT cells across mammalian evolution [Hsapiens_thymus_NKT]

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