Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Janis K. Burkhardt

Abstract

Ezrin, radixin, and moesin (ERM) family proteins regulate cytoskeletal responses bytethering the plasma membrane to the underlying actin cortex. Mutations in ERM proteins lead to severe combined immunodeficiency, but the function of these proteins in T cells remains poorly defined. Using mice in which T cells lack all ERM proteins, we demonstrate a selective role for these proteins in facilitating egress from lymphoid organs in response to sphingosine-1-phosphate (S1P), a pleiotropic signaling lipid abundant in the blood and lymph. ERM-deficient T cells display defective S1P-induced migration in vitro, despite normal responses to standard protein chemokines that control entry into and migration within lymphoid organs. Analysis of these defects revealed that S1P promotes a fundamentally different mode of migration than chemokines, characterized by intracellular pressurization and bleb-based motility. ERM proteins facilitate this process, controlling directional migration by limiting blebbing to the leading edge. We propose that the distinct modes of motility induced by S1P and chemokines are specialized to allow T cell migration across lymphatic barriers and through tissue stroma, respectively.

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Additional Files

V1. WT S1P chemokinesis 40FPS.mp4 (5577 kB)
V2. WT CCL19 Chemokinesis 40PS.mp4 (4944 kB)
V3. WT CXCL12 Chemokinesis 40FPS.mp4 (5431 kB)
V4. DKO S1P Chemokinesis 40FPS.mp4 (1600 kB)
V5. Lamellipodia to Bleb transition 1 Annotated 6FPS.mp4 (560 kB)
V6. Lamellipodia to Bleb transition 2 Annotated 6FPS.mp4 (1278 kB)
V7. DKO Blebs Poor Displacement Annotated 6FPS.mp4 (593 kB)
V8. DKO Blebs Poor Directionality Annotated 6FPS.mp4 (1282 kB)

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