Title

Expression and function of $\beta$2 integrins in the intestinal immune system

Date of Completion

January 1997

Keywords

Health Sciences, Immunology

Degree

Ph.D.

Abstract

The gut associated mucosa constitutes an integrated immune system comprised of secondary lymphoid organs and mucosal effector sites. Residing within the intestinal epithelium, intraepithelial lymphocytes (IEL) comprise a phenotypically and functionally unique peripheral T cell population. Phenotypically, the majority (90%) of IEL express CD8, in addition to either the TCR$\alpha\beta$ or TCR$\gamma\delta$. IEL are presumed to be important in the immunosurveillance of the epithelium. Colonization of the intestinal lumen by microbial flora results in the activation and expansion of IEL in situ. Despite such observations however, the molecules involved in the activation and migration of T cells in the IEL compartment remain largely unknown.^ In this study we initiated the identification of molecules that are unique to T cells of the intestinal epithelium. In so doing we have characterized the importance of two members of the $\beta$2 integrin adhesion molecule family in the establishment of the mucosal immune system. Within the intestinal epithelium, expression of p150,95 (CD11c/CD18) is detected on a high percentage of IEL expressing either the TCR$\alpha\beta$ or TCR$\gamma\delta$. Further analysis of gnotobiotic animals and animals expressing TCR of defined specificity demonstrated that the induction of p150,95 is both TCR-mediated and antigen specific.^ In contrast to expression of p150,95, expression of LFA-1 (CD11a/CD18) is expressed solely by TCR$\alpha\beta\sp+$ cells bearing CD8$\alpha\beta$, but not CD8$\alpha\alpha$. Oral infection with the facultative intracellular bacterium, L. monocytogenes, resulted in the up-regulation of p150,95 expression on both TCR$\alpha\beta$ and TCR$\gamma\delta$ IEL, which was particularly pronounced on IEL expressing CD8$\beta$. Moreover, examination of animals deficient in the expression of $\beta$2 integrins or the primary $\beta$2 integrin ligand, ICAM-1 (CD54), demonstrated the necessity for interactions between these molecules in the activation of TCR$\alpha\beta$ IEL, while an ICAM-1 independent $\beta$2 integrin interaction is involved in the activation of TCR$\gamma\delta$ IEL in vivo. Collectively, the results of this study demonstrate critical, yet differential, roles for LFA-1 and p150,95 during T cell responses in the intestinal mucosa. ^