EXTRATHYMIC T-CELL DIFFERENTIATION IN THE HUMAN INTESTINE EARLY IN LIFE

It is clear from experimental studies in mice that T cell maturation c an occur outside the thymus, especially in the intestine. There is lit tle sound evidence so far that extrathymic T cell maturation occurs to any significant extent in human gut, and, postnatally, there is abund ant evidence that the gut mucosa is an immune effector organ. Here, we describe a large population of T lymphocytes in human fetal intestina l mucosa that are proliferating (Ki67(+)) in the absence of foreign Ag (CD3(+), Ki67(+) lamina propria lymphocytes (LPL) 22 +/- 1.8% and CD3 +, Ki67+ intraepithelial lymphocytes (TEL) 9.1 +/- 1.4%), that express the T cell activation markers CD103, HLA-DR, and L-selectin(low), and that express mRNA transcripts for pre-TCR-alpha. There is also a subs tantial proportion of CD7(+) LPLs that do not express CD3 (CD3(-)7(+), 14 +/- 7% of all LPLs) in the fetal gut that may be differentiating i nto CD3(+) cells. Rearranged TCR-beta transcripts of fetal LPLs, IELs, and paired blood lymphocytes were cloned and sequenced, and virtually no overlap of clonality was observed between blood and intestine, sug gesting that gut T cells may not he derived from the blood. In additio n, 30 days after engraftment of SCID mice with fetal intestine, CD3(-) 7(+) cells, proliferating T cells, and pre-TCR-alpha transcripts were abundant, and there is a threefold increase in CD3(+) IELs. These data show that in the human intestine before birth a population of precurs or T cells exists that may be differentiating into mature T cells in s itu.