Late Postnatal Expansion of Self-reactive CD8 alpha alpha super(+) Intestinal Intraepithelial Lymphocytes in Mice

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 CD8 alpha alpha super(+) cells in adult H-Y TCR RAG super(-/-) male mice homozygous for the restricting MHC I allele, H-2D super(b). By contrast, in male mice heterozygous for the restricting and non-restricting MHC I allele, H-2D super(d) (MHC F sub(1), H-2D super(b/d)), IEL are composed of CD8 alpha beta and CD8 alpha alpha super(+) T cells. Here we demonstrate that IEL in the immediate postnatal period of MHC homozygous male mice were mostly CD8 super(-) T cells, while IEL in MHC F sub(1) male mice were CD8 super(-) and CD8 alpha beta super(+) T cells. Regardless of the MHC I configuration and the ability to support positive selection of CD8 alpha beta super(+) cells in the thymus, the expansion of CD8 alpha alpha super(+) IEL was a late postnatal event that followed a reduction in CD8 super(-) IEL. Furthermore, although in vivo treatment with the specific peptide antigen resulted in an earlier accumulation of activated IEL, the expansion of CD8 alpha alpha super(+) IEL remained inefficient until late in postnatal life. Finally, as CD8 super(-) IEL stimulated with TCR agonists in vitro, acquired expression of CD8 alpha alpha , we propose that CD8 alpha alpha super(+) IEL derive from CD8 super(-) IEL intermediates. Whether CD8 super(-) IEL are CD8 alpha beta -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 CD8 alpha alpha super(+) IEL are however, incomplete in the immediate postnatal intestine. Determining the factors required for the expansion or retention of CD8 alpha alpha super(+) IEL bearing high affinity, self-specific TCR will further elucidate the in vivo role of these T cells in intestinal homeostasis and perhaps, autoimmunity.