T Cell-mediated Rejection: Emerging Relationships — Puzzles and Paradoxes

12:25: Integrins and TCMR

Gregg A. Hadley, Ohio State University Medical Center, Columbus, USA

According to Wikipedia, integrins are cell surface receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the extracellular matrix (ECM). Integrins play critical roles in outside-in and inside-out cell signaling and thereby control diverse cellular processes including shape, mobility, and proliferation. An immense variety of different integrins exist, all of which are heterodimers comprising an alpha and a beta subunit. In mammals, no fewer than 18 alpha and 8 beta subunits have been identified. Of relevance to transplantation immunology, integrins play prominent roles in T cell activation, homing, and delivery of effector function. CD11a/beta 2 (LFA-1) is the prototypical integrin, which through recognition of its broadly expressed ligands, CD54 (ICAM-1), CD102 (ICAM-2), and CD50 (ICAM-3), plays a dominant role in T cell interactions with other leukocytes and the vascular endothelium . VLA family integrins, comprising at least six different alpha subunits associated with a common beta subunit, mediate T cell interactions with ECM proteins. The VLA-4 alpha subunit (CD49d) is unusual in that it pairs with either a beta 1 or beta 7 integrin subunit. Both heterodimers show dual specificity for vascular cell adhesion molecule-1 (VCAM-1) and fibronectin; CD49d/beta 7 additionally interacts with MAdCAM-1 expressed on the gut endothelium. A second beta 7 integrin (CD103/beta 7, formerly alpha E integrin), which is expressed by the majority of intraepithelial lymphocytes (IEL) and a subset of peripheral CD8 cells, recognizes the epithelial cell-specific ligand, E cadherin (L-CAM, uvomorulin). It is broadly accepted that CD103 serves as a homing receptor that targets IEL populations to the mucosal epithelium, but its role in peripheral CD8 T cell responses remains poorly defined. Together, T cell integrins dictate immune responses to transplanted tissues and thus constitute important targets for therapeutic intervention in transplant-associated immune sequelae.