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Hyaluronan binding by CD44 on T cells Maeshima, Nina Miharu


CD44 is a transmembrane protein that binds to hyaluronan, a component of the extracellular and pericellular matrices. Hyaluronan supports cell migration and proliferation during embryonic development, wound repair, as well as tumourigenesis. Hyaluronan binding to CD44 can also regulate leukocyte migration and adhesion. On naïve CD4 and CD8 T cells, CD44 is in its inactive form, but it is upregulated and induced to bind hyaluronan upon T cell activation. High CD44 expression is used as a marker for effector and memory T cells, and recent evidence has implicated CD44 in the formation of CD4 but not CD8 memory T cells. However, it is not clear if effector T cells bind hyaluronan and unknown if memory T cells bind hyaluronan. Hyaluronan binding has additionally been shown to mark a subset of the most suppressive regulatory CD4 T cells and here hyaluronan promotes FoxP3 expression, but the significance of why only a subset of these cells binds hyaluronan is unclear. Thus, the current understanding of when and on which cells hyaluronan binding is induced during an immune response, as well as its function on T cells, is incomplete. The first aim of this work was thus to determine when CD4 and CD8 T cells bind hyaluronan. T cells were activated in vitro with PMA and ionomycin and in vivo during an immune response to Listeria monocytogenes. Hyaluronan binding was assessed over a time course and found to occur on the mostly highly proliferative, activated T cells, as well as on a subset of memory T cells. The second aim of this work was to determine the consequences of binding hyaluronan. Hyaluronan binding on activated T cells was found to enhance their adhesion to fibronectin and inhibited both chemokinesis and chemokine-induced migration. Furthermore, hyaluronan induced chemokine-independent polarization of CD44, but inhibited CD44 co-polarization with phosphorylated ERM proteins. Together, the data suggests that hyaluronan binding is induced on highly proliferative T cells and may function as a stop signal for migration.

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