The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8 ⁺ T cells

Abstract

Cytotoxic T cell differentiation is guided by epigenome adaptations, but how epigenetic mechanisms control lymphocyte development has not been well defined. Here we show that the histone methyltransferase DOT1L, which marks the nucleosome core on active genes, safeguards normal differentiation of CD8+ T cells. T cell-specific ablation of Dot1L resulted in loss of naïve CD8+ T cells and premature differentiation toward a memory-like state, independent of antigen exposure and in a cell-intrinsic manner. Mechanistically, DOT1L controlled CD8+ T cell differentiation by ensuring normal T cell receptor density and signaling. DOT1L also maintained epigenetic identity, in part by indirectly supporting the repression of developmentally regulated genes. Finally, deletion of Dot1L in T cells resulted in an impaired immune response. Through our study, DOT1L is emerging as a central player in physiology of CD8+ T cells, acting as a barrier to prevent premature differentiation and controlling epigenetic integrity.

Histone methyltransferase DOT1L controls state‐specific identity during B cell differentiation

“…These findings show that DOT1L‐mediated H3K79me2 is a mark of many active genes in B cells, but suggest that only a small fraction of these genes requires H3K79me2 for maintenance of gene expression, since only a subset of the active genes was downregulated in Dot1L ‐KO B cells. Similar observations in transcriptome changes were also made in CD8 + T cells lacking DOT1L as well as upon DOT1L inhibition in mouse ES cells and during human cellular reprogramming (Kwesi‐Maliepaard et al , 2020; Ferrari et al , 2020; Kim et al , 2021).…”

Epigenetic regulation of T cell adaptive immunity

“…21 and in CD4 + and CD8 + SP compartments. 23 These alterations were also found to result in an increase in CD8 + T cells with a memory-like (CD44 + CD62L + ) phenotype. 23 Collectively, these findings served to establish epigenetic mechanisms as a critical regulatory process in the cell fate decisions that occur during T cell thymic development.…”

“…Conversely, a unique population of CD8 + TCR γδ + T cells were found to be enriched in the thymus, spleen, and lymph nodes of these mice in response to Dnmt1 loss 22 . Work by Kwesi‐Maliepaard et al reported that Lck ‐Cre‐mediated deletion of the H3K79 methyltransferase, disruptor of telomeric silencing 1‐like (DOT1L), in early T cell development resulted in a global loss of thymic cellularity with reductions in the double‐positive (DP) cells, and in CD4 + and CD8 + SP compartments 23 . These alterations were also found to result in an increase in CD8 + T cells with a memory‐like (CD44 + CD62L + ) phenotype 23 .…”

Hiding in Plain Sight: Virtually Unrecognizable Memory Phenotype CD8+ T cells

“…Although clearly important in the differentiation of T N cells to effector T cells and then in the establishment of antigen-specific memory, the role of histone post-translational modifications (PTMs) on T VM cell development and function is poorly studied. However, one key study has revealed an important role for the H3K79 methyltransferase, DOT1L, in T VM cell development [ 107 ]. In this study, it was demonstrated that, in the absence of DOT1L from T cells, almost all CD8 + T cells exhibited a T VM cell phenotype.…”

“…In this study, it was demonstrated that, in the absence of DOT1L from T cells, almost all CD8 + T cells exhibited a T VM cell phenotype. Due to the almost complete absence of circulating T N cells in these mice, the authors suggested a role for H3K79me in sustaining the naive state in CD8 + T cells, and that deletion of DOT1L may drive cells down a semi-differentiated state independently of antigen exposure [ 107 ]. These T VM -like cells also appeared during thymic development, suggesting that, similar to Bcl11b, Dot1L is required to suppress development of T cells down a T VM lineage.…”