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.
journal_name
Bloodjournal_title
Bloodauthors
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,Hdoi
10.1182/blood-2015-09-672428subject
Has Abstractpub_date
2016-04-14 00:00:00pages
1930-9issue
15eissn
0006-4971issn
1528-0020pii
blood-2015-09-672428journal_volume
127pub_type
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