Caveolin-1 regulates TCR signal strength and regulatory T-cell differentiation into alloreactive T cells
| Autor: | Anne Schönle, Gabriele Prinz, Anne Kathrin Hechinger, Frederike A. Hartl, Kerstin Fehrenbach, Keli Hippen, Jan Mentzel, Justus Duyster, Sebastian A. Wohlfeil, Susana Minguet, Ann Katrin Ruess, Dietmar Pfeifer, Robert Zeiser, Annette Schmitt-Graeff, Miguel A. del Pozo, Theresa Nöltner, Wolfgang Melchinger, Alessandro Prestipino, Katharina S. Rauch, Petya Apostolova, Marta C. Guadamillas, Marie Follo, Kristina Schachtrup, Bruce R. Blazar |
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| Jazyk: | angličtina |
| Předmět: |
CD4-Positive T-Lymphocytes
0301 basic medicine Regulatory T cell differentiation T-Lymphocytes Caveolin 1 Immunology Receptors Antigen T-Cell Graft vs Host Disease chemical and pharmacologic phenomena Biology Lymphocyte Activation T-Lymphocytes Regulatory Biochemistry Mice 03 medical and health sciences Interleukin 21 CD28 Antigens Transforming Growth Factor beta Animals Humans Transplantation Homologous Cytotoxic T cell Prospective Studies IL-2 receptor Phosphorylation Antigen-presenting cell Adaptor Proteins Signal Transducing Mice Inbred BALB C Transplantation ZAP70 T-cell receptor Hematopoietic Stem Cell Transplantation CD28 Cell Differentiation Forkhead Transcription Factors hemic and immune systems Cell Biology Hematology Cell biology Mice Inbred C57BL 030104 developmental biology Gene Expression Regulation cardiovascular system Signal Transduction |
| Zdroj: | Blood |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2015-09-672428 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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