Regulation of immune responses of the intestinal mucosa

The largest lymphoid organ in the body, the intestine, is also the most intriguing and complex. At its root, the gastrointestinal immune system must permit the absorption of nutrients while protecting against invasion of pathogens. In the process, it must sort through vast antigenic challenges and orchestrate an immune response appropriate to the occasion. Whereas the general outline of mucosal immunity has been defined with respect to the phenotype of the immune cells that compose the mucosal immune system, the ontogeny of these immune cells, and the regulation of IgA responses, the details that control mucosal T cell activation and suppression that coordinate this elaborate mucosal network continue to perplex. This review highlights unique aspects of T cell regulation within the intraepithelial lymphocyte (IEL) and lamina propria lymphocyte (LPL) compartments when compared with lymphocytes in the periphery. In general, IEL are largely extrathymically derived, have a limited TCR repertoire capable of recognizing common microbiologic Ags, and demonstrate predominantly cytolytic functions. LPL are thymically derived, highly activated lymphocytes with predominantly Th2 phenotype. LPL activation is distinct from classic memory T cells in their CD2/CD28 predominance that likely contributes to limiting TCR/CD3-mediated signals in the mucosa. Ag presentation in the gut may involve nonclassical, nonpolymorphic class I-like molecules expressed by epithelial cells that may positively select extrathymically derived lymphocyte populations as well as tolerize self-reactive lymphocytes. These special features of the mucosal immune system are integrated to downregulate immune responses to ubiquitous lumenal Ags.