Intestinal alpha beta T cells differentiate and rearrange antigen receptor genes in situ in the human infant.

ABSTRACT

Intestinal Ag exposure during neonatal life influences appropriate adult immune responses. To define the mechanisms shaping the T cell repertoire during this period, we examined T cell differentiation and receptor diversity in the intestine of human infants. Developmental phenotypes of intraepithelial and lamina propria intestinal T cells from infants aged 1 day to 2 years were assessed ex vivo by flow cytometry and in situ by triple-fluorescent immunohistochemistry. Gene recombination-specific enzymes were assessed by PCR. TCR beta-chain V region gene diversity was determined by sequencing. Several different early lineage T cell populations were present neonatally CD3(+)4(-)8(-) T cells were present at birth and numbers decreased during the neonatal period; CD3(+)4(+)8(+) T cells were present in low numbers throughout infancy; and CD3(+)4(+)8(-) or CD3(+)4(-)8(+) T cells increased with age. Very early lineage T cells, CD3(-)2(-)7(+) and CD3(-)2(+)7(+), were present neonatally, but were essentially absent at 1 year. Most lamina propria T cells differentiated rapidly after birth, but maturation of intraepithelial T cells took place over 1 year. Intestinal samples from infants less than 6 mo old contained transcripts of T early alpha and TdT, and 15 of 19 infant samples contained mRNA for RAG-1, some coexpressing RAG-2. TCR beta-chain repertoires were polyclonal in infants. Immature T cells, pre-T cells, and genes involved in T cell recombination were found in the intestine during infancy. T cell differentiation occurs within the neonatal human intestine, and the TCR repertoire of these developing immature T cells is likely to be influenced by luminal Ags. Thus, mucosal T cell responsiveness to environmental Ag is shaped in situ during early life.