CD8αα+ intraepithelial lymphocytes recruited from peripheral CD4+ and CD8+ T cells represent functionally distinct lineages

The TCRαβ CD8αα+ intraepithelial lymphocytes (IELs) play a significant role in primary immune defence in the small intestine. The canonical model of their development distinguishes TCRαβ IELs into induced and natural (TCRαβ CD8αα+) types, each influenced by distinct developmental pathways and antigen encounters. It is believed that natural CD8αα+ IELs differentiate solely from triple positive (TP) CD4+CD8αβ+CD8αα+ thymic progenitors that recognized self MHC-peptide complexes with high affinity but avoided deletion during selection. Our investigation reveals that, in addition to this central commitment, the CD8αα+ IELs undergo in situ enrichment through recruitment from peripheral CD4+ and CD8αβ+ T cell populations. We found that the functional makeup of individual clones within the CD8αα+ IEL subset is dictated by their origin. We demonstrate that expression of Bmp7 or Ly49 (Ly49C, F, H, and I) serve as markers indicating the CD8αα+ IELs’ peripheral provenance: CD8αβ+ and CD4+ T lymphocytes, respectively.