Physiological Chemistry of Integrin Function

New York University School Of Medicine, New York NY

Investigators

Linked publications & trials

Abstract

Lymphocytes are highly motile cells that move through secondary lymphoid tissues at high speed in response to chemokines, temporarily arrest migration through formation of an immunological synapse when they encounter antigen, and then renew rapid migration as effector cells with an autonomous mode of migration. Regulation of the physiological chemistry of integrins is essential at these three major stages. LFA-1 is a prototypical lymphocyte integrin, which undergoes dramatic changes in affinity when cells are activated by chemokines during steady state migration, when they are activated through their antigen receptors for immunological synapse formation, and when migrating on ICAM-1 bearing cells in later stages of activation and effector function. Our recent results demonstrate that the decision between immunological synapse formation and migration is controlled by the organization of LFA-1 in the contact area. The actinomyosin cortical cytoskeleton is known to be important for regulating integrin affinity and organization, but gaps in knowledge remain that must be filled in order to design effective immunotherapeutic interventions. We propose to 1) Determine the role of Rac and WAVE2 dendritic F-actin regulators in LFA-1 microcluster formation and their relationship to cell motility and immunological synapse formation;2) Determine how Cdc42 and WASp control the integrity of the pSMAC to regulate immunological synapse stability;and 3) Determine the potential of high-density presentation of chemokines to alter LFA-1 interaction affinity and pattern through RhoA mediated activation of myosin IIA. Throughout our work we will relate our findings to functional outcomes including signal integration, suppression by regulatory T cells, directed secretion by cytotoxic T cells and asymmetric cell division. Knowledge of how to control T cell migration and immunological synapse stability through manipulation of LFA-1 molecular and supramolecular chemistry have potential applications in treatment of autoimmune disease and allergy and the development of synthetic vaccines with improved efficacy.