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

• Published in: Blood 2016-04, Vol.127 (15), p.1930-1939
• Main Authors: 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, Angel del Pozo, Miguel, Schmitt-Graeff, Annette, Duyster, Justus, Hippen, Keli I., Blazar, Bruce R., Schachtrup, Kristina, Minguet, Susana, Zeiser, Robert
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Animals; Caveolin 1 - genetics; Caveolin 1 - metabolism; Caveolin 1 - physiology; CD28 Antigens - metabolism; CD4-Positive T-Lymphocytes - cytology; Cell Differentiation; Forkhead Transcription Factors - metabolism; Gene Expression Regulation; Graft vs Host Disease - immunology; Hematopoietic Stem Cell Transplantation; Humans; Lymphocyte Activation - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Phosphorylation; Prospective Studies; Receptors, Antigen, T-Cell - metabolism; Signal Transduction; T-Lymphocytes - cytology; T-Lymphocytes, Regulatory - cytology; Transforming Growth Factor beta - metabolism; Transplantation; Transplantation, Homologous
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2015-09-672428

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. •Cav-1–deficient T cells preferentially differentiate into Tregs, which translates into lower GVHD severity in mice.•Reduced TCR:Lck clustering in Cav-1–deficient T cells is responsible for reduced TCR downstream signaling events promoting Treg differentiation.