A subpopulation of T cells (intraepithelial lymphocytes (IEL)) bind to the basolateral surfaces of adjacent polarized epithelial cells in the intestine. We (and others) found that IEL express preferentially the alpha-E-beta-7 integrin complex. We derived a cDNA clone corresponding to the gene that encodes alpha-E and showed it predicts an alpha chain with an 'I' domain and a novel extra ('X') domain not found in any other integrin gene. Using static cell-to-cell adhesion assays, we showed that mAb against alpha-E-beta-7 block specifically T cell adhesion to epithelial cell monolayers. To identify the epithelial counter-receptor for the alpha-E-beta-7 integrin, we produced mAb against epithelial cells that block IEL-to-epithelial cell adhesion. These mAb recognized E- cadherin. We showed that transfection of expression constructs encoding alpha-E-beta-7 (but not alpha-4-beta-7) conferred adhesiveness upon the COS cell recipients for binding to E-cadherin transfected (but not mock transfected) L-cells. In order to gain insight into the nature of this interaction, we propose to study directly the binding of alpha-E-beta-7 and E-cadherin polypeptides (Aim l). Then, mutant and chimeric molecules will be produced to elucidate the regions of each molecule that participate in recognition of their counter-receptors (Aims II and III). Finally, biochemical analysis revealed the existence of a catenin-associated cadherin-like molecule on T lymphocytes. We propose (Aim IV) to determine the nature of this molecule and develop mAb and gene probes that will be useful in examining its function. This is the first example of an integrin-cadherin interaction. It carries potentially important implications for immune surveillance and autoimmunity by providing insight into the tissue specific localization of lymphocytes in the gastrointestinal and respiratory tracts, and at other mucosal surfaces.
|Bry, Lynn; Brigl, Manfred; Brenner, Michael B (2006) CD4+-T-cell effector functions and costimulatory requirements essential for surviving mucosal infection with Citrobacter rodentium. Infect Immun 74:673-81|
|Bry, Lynn; Brenner, Michael B (2004) Critical role of T cell-dependent serum antibody, but not the gut-associated lymphoid tissue, for surviving acute mucosal infection with Citrobacter rodentium, an attaching and effacing pathogen. J Immunol 172:433-41|
|Dodge, Ingrid L; Carr, Michelle Woldemar; Cernadas, Manuela et al. (2003) IL-6 production by pulmonary dendritic cells impedes Th1 immune responses. J Immunol 170:4457-64|