Role of gut cryptopatches in early extrathymic maturation of intestinal intraepithelial T cells

Lympho-hemopoietic progenitors residing in murine gut cryptopatches (CP) have been shown to generate intestinal intraepithelial T cells (IEL), To investigate the role of CP in progenitor maturation, we analyzed IEL in male mice with a truncated mutation of common cytokine receptor gamma-chain (CR gamma(-/Y)) in which CP were undetectable, IEL-expressing TCR-gamma delta (gamma delta-IEL) were absent, and a drastically reduced number of Thy-1highCD4(+) and Thy-1(high)CD8 alpha beta(+) alpha beta-IEL were present in CR gamma(-/Y) mice, whereas these alpha beta-IEL disappeared from athymic CR gamma(-/Y) littermate mice. Athymic CR gamma(-/Y) mice possessed a small TCR- and alpha(E)beta(7) integrin-negative IEL population, characterized by the disappearance of the extrathymic CD8 alpha alpha(+) subset, that expressed pre-T alpha, RAG-2, and TCR-C beta but not CD3 epsilon transcripts. These TCR- IEL from athymic CR gamma(-/Y) mice did not undergo D beta-J beta and V delta-J delta joinings, despite normal rearrangements at the TCR-beta and -delta loci in thymocytes from euthymic CR gamma(-/Y) mice. In contrast, athymic severe combined immunodeficient mice in which CP developed normally possessed two major TCR(-)alpha(E)beta(7)(+) CD8 alpha alpha(+) and CD8(-) TEL populations that expressed pre-T alpha, RAG-2, TCR-C beta, and CD3 epsilon transcripts. These findings underscore the role of gut CP in the early extrathymic maturation of CD8 alpha alpha(+) IEL, including cell-surface expression of alpha(E)beta(7) integrin, CD3 epsilon gene transcription, and TCR gene rearrangements.