Transmission Of Integrin Beta 7 Transmembrane Domain Topology Enables Gut Lymphoid Tissue Development

Integrin activation regulates adhesion, extracellular matrix assembly, and cell migration, thereby playing an indispensable role in development and in many pathological processes. A proline mutation in the central integrin beta 3 transmembrane domain (TMD) creates a flexible kink that uncouples the topology of the inner half of the TMD from the outer half. In this study, using leukocyte integrin alpha 4 beta 7, which enables development of gut-associated lymphoid tissue (GALT), we examined the biological effect of such a proline mutation and report that it impairs agonist-induced talin-mediated activation of integrin alpha 4 beta 7, thereby inhibiting rolling lymphocyte arrest, a key step in transmigration. Furthermore, the alpha 4 beta 7(L721P) mutation blocks lymphocyte homing to and development of the GALT. These studies show that impairing the ability of an integrin beta TMD to transmit talin-induced TMD topology inhibits agonist-induced physiological integrin activation and biological function in development.