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.
Bibliographical noteFunding Information:
This study was supported by grants from the Else Kr?ner Fresenius Stiftung (2013-A04) (R.Z. and S.M.) and (DFG SFB1160 [P14 to R.Z. and P5 to S.M.]); R.Z. is funded by a Heisenberg Professorship (DFG ZE 872/3-1) and ERC Consolidator grant (681012 GvHDCure); K.S.R. is funded by an International Graduate Academy fellowship; K.S. is funded by the Federal Ministry of Education and Research grant (BMBF 01EO1303); and B.R.B. is funded by the National Institutes of Health, National Heart, Lung, and Blood Institute (R01 HL11879).
© 2016 by The American Society of Hematology.