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

Anne Schönle, Frederike A. Hartl, Jan Mentzel, Theresa Nöltner, Katharina S. Rauch, Alessandro Prestipino, Sebastian A. Wohlfeil, Petya Apostolova, Anne Kathrin Hechinger, Wolfgang Melchinger, Kerstin Fehrenbach, Marta C. Guadamillas, Marie Follo, Gabriele Prinz, Ann Katrin Ruess, Dietmar Pfeifer, Miguel Angel Del Pozo, Annette Schmitt-Graeff, Justus Duyster, Keli I. HippenBruce R. Blazar, Kristina Schachtrup, Susana Minguet, Robert Zeiser

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24 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1930-1939
Number of pages10
JournalBlood
Volume127
Issue number15
DOIs
StatePublished - Apr 14 2016

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    Schönle, A., Hartl, F. A., Mentzel, J., Nöltner, T., Rauch, K. S., Prestipino, A., Wohlfeil, S. A., Apostolova, P., Hechinger, A. K., Melchinger, W., Fehrenbach, K., Guadamillas, M. C., Follo, M., Prinz, G., Ruess, A. K., Pfeifer, D., Del Pozo, M. A., Schmitt-Graeff, A., Duyster, J., ... Zeiser, R. (2016). Caveolin-1 regulates TCR signal strength and regulatory T-cell differentiation into alloreactive T cells. Blood, 127(15), 1930-1939. https://doi.org/10.1182/blood-2015-09-672428