Late Postnatal Expansion of Self-reactive CD8αα+ Intestinal Intraepithelial Lymphocytes in Mice*

Abstract

The intestinal epithelium is unique in that it harbors auto-reactive T cells largely absent from the peripheral TCR repertoire in normal mice. Intestinal intraepithelial lymphocytes (IEL) expressing self-reactive TCR are mostly CD8αα+ cells in adult H-Y TCR RAG−/− male mice homozygous for the restricting MHC I allele, H-2Db. By contrast, in male mice heterozygous for the restricting and non-restricting MHC I allele, H-2Dd (MHC F1, H-2Db/d), IEL are composed of CD8αβ and CD8αα+ T cells. Here we demonstrate that IEL in the immediate postnatal period of MHC homozygous male mice were mostly CD8− T cells, while IEL in MHC F1 male mice were CD8− and CD8αβ+ T cells. Regardless of the MHC I configuration and the ability to support positive selection of CD8αβ+ cells in the thymus, the expansion of CD8αα+ IEL was a late postnatal event that followed a reduction in CD8− IEL. Furthermore, although in vivo treatment with the specific peptide antigen resulted in an earlier accumulation of activated IEL, the expansion of CD8αα+ IEL remained inefficient until late in postnatal life. Finally, as CD8− IEL stimulated with TCR agonists in vitro, acquired expression of CD8αα, we propose that CD8αα+ IEL derive from CD8− IEL intermediates. Whether CD8− IEL are CD8αβ-lineage cells that escape deletion in the thymus or are T cells targeted to the intestine from the thymus because of the early and high level TCR transgene expression in this model, is not clear. The signals required for the expansion of CD8αα+ IEL are however, incomplete in the immediate postnatal intestine. Determining the factors required for the expansion or retention of CD8αα+ IEL bearing high affinity, self-specific TCR will further elucidate the in vivo role of these T cells in intestinal homeostasis and perhaps, autoimmunity.