Caveolin-1 regulates TCR signal strength and regulatory T-cell differentiation into alloreactive T cells.

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Blood, ISSN: 1528-0020, Vol: 127, Issue: 15, Page: 1930-9

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Schönle, Anne, Hartl, Frederike A, Mentzel, Jan, Nöltner, Theresa, Rauch, Katharina S, Prestipino, Alessandro, Wohlfeil, Sebastian A, Apostolova, Petya, Hechinger, Anne-Kathrin, Melchinger, Wolfgang, Fehrenbach, Kerstin, Guadamillas, Marta C, Follo, Marie, Prinz, Gabriele, Ruess, Ann-Katrin, Pfeifer, Dietmar, del Pozo, Miguel Angel, Schmitt-Graeff, Annette, Duyster, Justus, Hippen, Keli I, Blazar, Bruce R, Schachtrup, Kristina, Minguet, Susana, Zeiser, Robert Show More Hide
American Society of Hematology
Immunology and Microbiology, Biochemistry, Genetics and Molecular Biology, Medicine
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Caveolin-1 (Cav-1) is a key organizer of membrane specializations and a scaffold protein that regulates signaling in multiple cell types. We found increased Cav-1 expression in human and murine T cells after allogeneic hematopoietic cell transplantation. Indeed, Cav-1(-/-)donor T cells caused less severe acute graft-versus-host disease (GVHD) and yielded higher numbers of regulatory T cells (Tregs) compared with controls. Depletion of Tregs from the graft abrogated this protective effect. Correspondingly, Treg frequencies increased when Cav-1(-/-)T cells were exposed to transforming growth factor-β/T-cell receptor (TCR)/CD28 activation or alloantigen stimulation in vitro compared with wild-type T cells. Mechanistically, we found that the phosphorylation of Cav-1 is dispensable for the control of T-cell fate by using a nonphosphorylatable Cav-1 (Y14F/Y14F) point-mutation variant. Moreover, the close proximity of lymphocyte-specific protein tyrosine kinase (Lck) to the TCR induced by TCR-activation was reduced in Cav-1(-/-)T cells. Therefore, less TCR/Lck clustering results in suboptimal activation of the downstream signaling events, which correlates with the preferential development into a Treg phenotype. Overall, we report a novel role for Cav-1 in TCR/Lck spatial distribution upon TCR triggering, which controls T-cell fate toward a regulatory phenotype. This alteration translated into a significant increase in the frequency of Tregs and reduced GVHD in vivo.

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