Molecular architecture of lymphocyte cortex

Division Of Basic Sciences - Nci

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Abstract

Class I myosins, which link F-actin to membrane, are largely undefined in lymphocytes. We have previously identified Myo1G as the dominant class I myosin in T-lymphocytes, demonstrated its preferential localization at the plasma membrane, and performed structure/function analysis to elucidate the structural basis of its association with the plasma membrane. In the study period we have emphasized analysis of its function by generating a Myo1G knockout mouse and investigating the functional alterations in that mouse. We find that overall immune system development is generally normal. However, when we initiated more targeted hypotheses testing, notable alterations were observed. Knockout T-lymphocytes have clearly INCREASED migration rates. Initial analysis reveals a 30% increase in rate of in vitro migration on planar surfaces coated with ICAM-1. In vivo studies were then undertaken of T-lymphocyte migration in lymph nodes. Those studies demonstrated a 40% increase in rate of migration. We explored potential mechanisms by which Myo1G could regulate migration. We hypothesized that Myo1G would regulate membrane tension in lymphocytes and established a collaboration with Dr. Matthew Tyska (Vanderbilt) to directly test the impact of Myo1G deletion on membrane tension. The results demonstrate that Myo1G knockouts have about a 50% decrease in membrane tension. Given the constraints that membrane tension place on lamellipod extension, we view this decrease in membrane tension as a likely major contributor to the accelerated migration observed in our Myo1G knockout mice