Berzins, S. P. | bioRxiv Science

bioRxiv2026

Dynamic remodeling of chromatin during human mucosal-associated invariant T cell development

T cell development in the thymus is a tightly regulated process where epigenetic modifications, such as histone 3 lysine 27 acetylation (H3K27ac), play a crucial role in controlling the activation of genes. The epigenetic regulation of human mucosal-associated invariant T (MAIT) cell development is unknown; we mapped the regulatory chromatin landscape in the three developmental stages of thymic MAIT cells to identify the regulatory elements and enhancer activity involved in thymic maturation and analysed whether these chromatin dynamics are associated with the acquisition of effector programs in developing MAIT cells. Utilising cleavage under target and tagmentation (CUT&Tag), genome-wide H3K27ac profiles were generated and combined with transcriptome data from thymic MAIT cells, which revealed how developmental shifts in enhancer activity correspond to changes in gene expression. In total, 41,958 genomic regions with H3K27ac signal were identified in MAIT cells across the three development stages, of which 1,200 regions showed acetylation changes during differentiation from stage 1 to stage 3. At dynamic regions, the greatest differences were observed between stage 1 and stage 3, highlighting a progressive gain or loss of H3K27ac during MAIT cell development. Overall, MAIT cell maturation was associated with the gradual accumulation of H3K27ac at promoters and enhancers, which closely correlated with gene expression changes during development. Stage-specific enrichment of H3K27ac was observed at key transcription factor gene loci involved in MAIT cell development, including ZBTB16 (PLZF), EOMES, RUNX3, NFATC2, FOXO1, TGIF1, IRF1, and MAF genes. Epigenetic remodelling was also observed at cytokine and cytokine receptors (IL7R, IL18R1, IL23R, IFNG), chemokines and chemokine receptors (CCL4, CCL5, CCR5, CCR9, CXCR4, CXCR6), as well as several surface molecules with known immunological function. Our work reveals a previously uncharacterised epigenetic profile of human MAIT cells that regulates and inuences their development.

immunology↗

bioRxiv2024

The Changing Immune Landscape of Innate-like T Cells and Innate Cells Throughout Life

Spectral flow cytometry is an advanced immunological tool that enables comprehensive analysis of the immune system by simultaneously comparing innate and adaptive immune cells. Here, using a 40-colour antibody panel we advance our knowledge of innate and innate-like T cells by investigating chemokine receptors, activation and maturation markers not usually assessed on these populations and examine age-related effects to these immune cell subsets. We characterised phenotypic changes of peripheral blood mononuclear cells (PBMC) in three age groups: newborn (cord blood), adults aged 20-30 years, and adults aged 70-80 years, focusing on innate-like T cells and innate cells, including MAIT cells, NKT cells, {gamma}{delta} T cells, ILCs, and Natural Killer (NK) cells. We identify subsets of double-negative (DN) T cells (CD4- CD8-) and CD161+ T cells that increase in an age-related manner and exhibit a phenotype similar to innate-like T cells, MAIT cells and {gamma}{delta} T cells. Innate-like T cell subsets express similar patterns of the chemokine receptors and maturation markers CCR4, CCR6, CD27, CD38, CD57 and CD45RA, and resemble memory subsets of conventional CD4+ T cells and CD8+ T cells. We could detect ILCs in all age ranges, although the frequency of ILC1, ILC2, and ILC3 subsets decreased with age. Notably, we identify the NK maturation marker, CD57, as a universal marker that defines ageing populations of innate and adaptive immune cells. This study enhances our understanding of the ontogeny of human immune cells, highlighting significant age-related changes in the frequency and phenotype of immune cells.

immunology↗