Niche-specific MHC II and PD-L1 regulate CD4⁺CD8αα⁺ intraepithelial lymphocyte differentiation

Conventional CD4⁺ T cells are differentiated into CD4⁺CD8αα⁺ intraepithelial lymphocytes (IELs) in the intestine; however, the roles of intestinal epithelial cells (IECs) are poorly understood. Here, we showed that IECs expressed MHC class II (MHC II) and programmed death-ligand 1 (PD-L1) induced by the microbiota and IFN-γ in the distal part of the small intestine, where CD4⁺ T cells were transformed into CD4⁺CD8αα⁺ IELs. Therefore, IEC-specific deletion of MHC II and PD-L1 hindered the development of CD4⁺CD8αα⁺ IELs. Intracellularly, PD-1 signals supported the acquisition of CD8αα by down-regulating the CD4-lineage transcription factor, T helper-inducing POZ/Krüppel-like factor (ThPOK), via the Src homology 2 domain-containing tyrosine phosphatase (SHP) pathway. Our results demonstrate that noncanonical antigen presentation with cosignals from IECs constitutes niche adaptation signals to develop tissue-resident CD4⁺CD8αα⁺ IELs.