RESUMO
The activation and specialization of regulatory T cells (Tregs) are crucial for maintaining immune self-tolerance; however, the regulation of these processes by histone modifications is not fully understood. Here, we show that T cell-specific deletion of the lysine methyltransferase MLL1 results in a spontaneous lymphocyte proliferation phenotype in aged mice without disturbing the development of conventional T cells and Tregs. Treg-specific MLL1 ablation leads to a systemic autoimmune disease associated with Treg dysfunction. Moreover, RNA sequencing demonstrates that the induction of multiple genes involved in Treg activation, functional specialization, and tissue immigration is defective in MLL1-deficient Tregs. This dysregulation is associated with defects in H3K4 trimethylation at these genes' transcription start sites. Finally, using a T-bet fate-mapping mouse system, we determine that MLL1 is required to establish stable Th1-type Tregs. Thus, MLL1 is essential in optimal Treg function by providing a coordinated chromatin context for activation and specialization.
Assuntos
Histona-Lisina N-Metiltransferase , Ativação Linfocitária , Proteína de Leucina Linfoide-Mieloide , Linfócitos T Reguladores , Animais , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteína de Leucina Linfoide-Mieloide/genética , Camundongos , Camundongos Endogâmicos C57BL , Histonas/metabolismo , Proteínas com Domínio T/metabolismo , Proteínas com Domínio T/genética , Metilação , Proliferação de CélulasRESUMO
Foxp3 is the master transcription factor for regulatory T cells (Tregs). Alternative splicing of human Foxp3 results in the expression of two isoforms: the full length and an exon 2-deleted protein. Here, AlphaFold2 predictions and in vitro experiments demonstrate that the N-terminal domain of Foxp3 inhibits DNA binding by moving toward the C terminus and that this movement is mediated by exon 2. Consequently, we find that Foxp3Δ2-bearing thymus-derived Tregs (tTregs) in the peripheral lymphoid organ are less sensitive to T cell receptor (TCR) stimulation due to the enhanced binding of Foxp3Δ2 to the Batf promoter and are hyporesponsive to interleukin-2 (IL-2). In contrast, among RORγt+ peripherally induced Tregs (pTregs) in the large intestine, Foxp3Δ2 pTregs express many more RORγt-related genes, conferring a competitive advantage. Together, our results reveal that alternative splicing of exon 2 generates an active form of Foxp3, which plays a differential role in regulating tTreg and pTreg homeostasis.