Extrathymic TCR Gene Rearrangement in Human Small Intestine: Identification of New Splice Forms of Recombination Activating Gene-1 mRNA with Selective Tissue Expression

Abstract

Two new 5′-untranslated region (5′UTR) exons were identified in the human gene for the lymphocyte-specific endonuclease recombination activating gene-1 (RAG1) required for the somatic recombination yielding functional Ag receptors. These 5′UTR exons were used in three different splice forms by jejunal lymphocytes of the T cell lineage. RAG1 mRNA containing the previously described 5′UTR exon was not expressed in these cells. Conversely, one of the new 5′UTR exons was not expressed in thymus. The new RAG1 mRNA splice forms were all expressed in immature T cells (CD2+CD7+CD3−). This cell population also expressed high levels of mRNA for the pre-T α-chain. In situ hybridization demonstrated jejunal cells expressing the new splice forms of RAG1 mRNA, both intraepithelially and in lamina propria. Pre-T α-chain mRNA-expressing cells were detected at the same sites. These results strongly suggest ongoing TCR gene rearrangement in human small intestinal mucosa, yielding T cells specially adapted for this environment. This seems to be achieved by two parallel processes, extrathymic T cell development and peripheral Ag-driven TCR editing.