The effector differentiation of TCRαβ⁺CD8αα⁺ intraepithelial lymphocytes is reciprocally regulated by BCL6 and BLIMP1

CD8αα⁺TCRαβ⁺ intraepithelial lymphocytes (IELs) play crucial roles in maintaining intestinal homeostasis and host protection. However, the functional regulation of these cells remains unclear. Here, we have discovered and characterized two distinct developmental stages within intestinal CD8αα⁺ αβ IELs: a stem-like, defined by BCL6, TCF1, and CD160 expression, and an effector-like, with granzyme B expression and Prdm1 transcription. The differentiation from stem-like to effector-like CD8αα⁺ αβ IELs is promoted by T cell receptor (TCR) and IL-12 signaling and is controlled by the opposing actions of BCL6 and BLIMP1. Loss of BCL6 promotes the development of effector-like CD8αα⁺ αβ IELs, leading to increased effector molecule expression and heightened inflammation under dextran sodium sulfate (DSS)-induced colitis. In contrast, BLIMP1 deficiency perturbs the effector differentiation and reduces the susceptibility to gut inflammation. Our study thus reveals a critical antagonistic function between BCL6 and BLIMP1 in governing the fate decisions of CD8αα⁺ αβ IEL subsets.