Two mechanisms of beta1 integrin regulation in human leukocytes.

Abstract

Cell adhesion plays a fundamental role in controlling normal cellular behavior. Integrins are a large family of adhesion molecules that play an important role in mediating lymphocyte interactions with other cells and with components of the extracellular matrix. The distinct array of integrins expressed on the surface of a cell at any given time dictate the spectrum of ECM and cell surface ligands with which the cell can interact. Changes in integrin expression can dramatically affect lymphocyte recirculation and activation. Unlike most cell types in the body that continuously stay in a distinct anatomical location, cells of the immune system require the ability to alternate between adhesive and nonadhesive states in order to function properly. Normal lymphocyte recirculation requires that cells be in a relatively nonadherent state so that rapid movement throughout the vascular and lymphatic systems is not impeded. Movement of cells into peripheral lymphoid organs and other tissues, where antigen recognition occurs, involves a multi-step adhesion process that allows circulating cells to slow down and extravasate through the vascular endothelium. This thesis addresses two important mechanisms that influence lymphocyte adhesion: (1) regulation of cell surface $\beta$1 integrin expression and (2) activation-dependent regulation of $\beta$1 integrin function. Results using normal Jurkat T cells and $\alpha$4-deficient Jurkat cells have suggested potential mechanisms that might be used by lymphocytes to regulate cell surface expression of $\beta$1 integrins. These studies indicate that expression of individual $\alpha$ subunits may be regulated differently in lymphocytes. Our results suggest a role for both post-transcriptional and post-translation control of $\alpha$2 subunit protein expression and a role for post-transcriptional regulation of the $\alpha$5 subunit. In addition, re-expression experiments suggest that the presence of $\alpha$4 protein may influence cell surface expression of other a subunits. Studies with HL60 transfectants expressing CD2/28 chimeric receptors have implicated phosphatidylinositol 3-kinase (PI 3-K) as playing an important role in the ability of CD28 to regulate integrin-mediated adhesion. However, substitution of the CD28 SH2-binding motif YMNM with the YVKM motif from CTLA-4 indicated that recruitment and activation of PI 3-K is not a sufficient signal to upregulate $\beta$1 integrin-mediated adhesion since this receptor could still mediate PI 3-K activation but not integrin upregulation.