Caveolin-1 regulates TCR signal strength and regulatory T-cell differentiation into alloreactive T cells
Schönle A, Hartl FA, Mentzel J, Nöltner T, Rauch KS, Prestipino A, Wohlfeil SA, Apostolova P, Hechinger AK, Melchinger W, Fehrenbach K, Guadamillas MC, Follo M, Prinz G, Ruess AK, Pfeifer D, del Pozo MA, Schmitt-Graeff A, Duyster J, Hippen KI, Blazar BR, Schachtrup K, Minguet S, Zeiser R.
Caveolin-1 (CAV1) is a key organizer of membrane specializations and a scaffold protein that regulates signaling in multiple cell types. We found here increased CAV1 expression in human and murine T cells after allogeneic hematopoietic cell transplantation. Indeed, Cav1-/- 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 Cav1-/- 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 CAV1 is dispensable for the control of T-cell fate by using a novel nonphosphorylatable CAV1 (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 Cav1-/- 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 CAV1 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. Our results provide both a molecular mechanism and a conceptual framework for how plasma membrane nanoorganization regulates signal transduction and cell fate.
