BCL6 is required for the thymic development of TCRαβ + CD8αα + intraepithelial lymphocyte lineage.

TCRαβ ⁺ CD8αα ⁺ intraepithelial lymphocytes (CD8αα ⁺ αβ 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 αβ T cells resulted in the near absence of CD8αα ⁺ αβ IELs. BCL6 was expressed by approximately 50% of CD8αα ⁺ αβ 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 CD8αα ⁺ αβ IELs.