Thymus-independent development and negative selection of T cells expressing T cell receptor α/β in the intestinal epithelium: Evidence for distinct circulation patterns of gut- and thymus-derived T lymphocytes

Abstract

We demonstrate that mouse intestinal intraepithelial lymphocytes (IEL) can be divided into subsets based on the differential expression of functional T cell receptor α/β (TCR-α/β) signaling complexes. Two subsets, CD4+8α+β- and CD8α+β-, are refractory to stimulation with antiTCR-α/β and contain high frequencies of potentially self-reactive cells. In contrast, the CD4+ and CD8α+β+ IEL subsets are responsive to anti-TCR-α/β and depleted of potentially self-reactive cells. The analysis of fetal liver radiation chimeras using adult thymectomized recipients demonstrates that the four TCR-α/β+ IEL subsets are generated in normal numbers in the absence of the thymus. Moreover, expression of the major histocompatibility complex class II-encoded I-E molecule and Mls1a in the gut of the athymic host results in the negative selection of potentially self-reactive T cells expressing Vβ11 and Vβ6, respectively, from those IEL subsets that express functional TCR-α/β signaling complexes. Neither the spleen nor the Peyer's patches of athymic recipients contain T cells of donor origin. In contrast, normal numbers of phenotypically and functionally mature CD4+ and CD8α+β+ T cells of donor origin are found in the lamina propria of chimeric animals. The phenotypic analysis of lymphocytes obtained from Ly5 congenic parabionts reveals that peripheral T cells migrate rapidly to the Peyer's patches and lamina propria, but not to the intestinal epithelium. Taken together, these results demonstrate that the intestinal epithelium is a thymus-independent site of T lymphopoiesis, where selection of the T cell repertoire involves the deletion of potentially self-reactive cells in situ. Moreover, the appearance of donor-derived, phenotypically mature T cells, exclusively in the lamina propria of athymic radiation chimeras, suggests that mature IEL expressing functional TCR-α/β migrate to this site.