T-cell development and selection in the intestinal epithelium

Though it is now well established that T lymphocytes develop in the murine intestinal epithelium, many features of T lymphopoiesis occurring at this site remain controversial and poorly understood. One of the most contentious issues is whether all TcR alpha beta+ iIEL subsets, characterized by the differential expression of CD4, CD8 alpha and CD8 alpha, develop in situ, as suggested by the analysis of athymic radiation chimeras and parabionts. Athymic radiation chimeras have also been used to study positive and negative selection events imposed on developing iIEL expressing an MHC class I restricted transgenic TcR alpha beta. Results reveal that while distinct mechanisms may regulate these processes in the gut, the functional repertoire generated at this site is identical to that resulting from intra-thymic T-cell development. Strikingly, this is not the case for the development and selection of iIEL expressing an MHC class II restricted TcR alpha beta. Features peculiar to MHC class II molecules expressed by enterocytes are discussed in this context. In addition, two model systems are presented towards understanding the basis for the observed oligoclonal repertoire of TcR alpha beta+ iIEL. Specifically, the role of luminal antigen is addressed by comparing the repertoire of iIEL developing in the orthotopic gut with that of iIEL developing in an ectopic sterile intestine in the same athymic animal. The role of TcR alpha beta-mediated signals in support of the putative oligoclonal expansion of iIEL, is addressed using mice lacking the protein tyrosine kinase, Lck.