BCL6 is required for the thymic development of TCR⁺CD8⁺ intraepithelial lymphocyte lineage

TCR alpha beta(+)CD8 alpha alpha(+) intraepithelial lymphocytes (CD8 alpha alpha(+) alpha beta IELs) are a specialized subset of T cells in the gut epithelium that develop from thymic agonist selected IEL precursors (IELps). The molecular mechanisms underlying the selection and differentiation of this T cell type in the thymus are largely unknown. Here, we found that Bcl6 deficiency in alpha beta T cells resulted in the near absence of CD8 alpha alpha(+) alpha beta IELs. BCL6 was expressed by approximately 50% of CD8 alpha alpha(+) alpha beta IELs and by the majority of thymic PD1(+ )IELps after agonist selection. Bcl6 deficiency blocked early IELp generation in the thymus, and its expression in IELps was induced by thymic TCR signaling in an ERK-dependent manner. As a result of Bcl6 deficiency, the precursors of IELps among CD4(+)CD8(+) double-positive thymocytes exhibited increased apoptosis during agonist selection and impaired IELp differentiation and maturation. Together, our results elucidate BCL6 as a crucial transcription factor during the thymic development of CD8 alpha alpha(+) alpha beta IELs.