title: Caveolin-1 regulates TCR signal strength and regulatory T-cell differentiation into alloreactive T cells.
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.
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center, Freiburg, Germany; Faculty of Biology, Albert-Ludwigs University, Freiburg, Germany;
authors.forename: Anne
authors.initials: A
authors.lastname: Schönle
authors.affiliation: Faculty of Biology, Albert-Ludwigs University, Freiburg, Germany;
authors.forename: Frederike A
authors.initials: FA
authors.lastname: Hartl
authors.affiliation: Faculty of Biology, Albert-Ludwigs University, Freiburg, Germany;
authors.forename: Jan
authors.initials: J
authors.lastname: Mentzel
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center, Freiburg, Germany;
authors.forename: Theresa
authors.initials: T
authors.lastname: Nöltner
authors.affiliation: Faculty of Biology, Albert-Ludwigs University, Freiburg, Germany; Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany;
authors.forename: Katharina S
authors.initials: KS
authors.lastname: Rauch
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center, Freiburg, Germany; Faculty of Biology, Albert-Ludwigs University, Freiburg, Germany;
authors.forename: Alessandro
authors.initials: A
authors.lastname: Prestipino
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center, Freiburg, Germany;
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Wohlfeil
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center, Freiburg, Germany;
authors.forename: Petya
authors.initials: P
authors.lastname: Apostolova
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center, Freiburg, Germany; Faculty of Biology, Albert-Ludwigs University, Freiburg, Germany;
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Hechinger
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center, Freiburg, Germany;
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Melchinger
authors.affiliation: Faculty of Biology, Albert-Ludwigs University, Freiburg, Germany;
authors.forename: Kerstin
authors.initials: K
authors.lastname: Fehrenbach
authors.affiliation: Integrin Signalling Laboratory, Cell Biology and Physiology Program, Cell and Developmental Biology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain;
authors.forename: Marta C
authors.initials: MC
authors.lastname: Guadamillas
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center, Freiburg, Germany;
authors.forename: Marie
authors.initials: M
authors.lastname: Follo
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center, Freiburg, Germany;
authors.forename: Gabriele
authors.initials: G
authors.lastname: Prinz
authors.affiliation: Faculty of Biology, Albert-Ludwigs University, Freiburg, Germany;
authors.forename: Ann-Katrin
authors.initials: AK
authors.lastname: Ruess
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center, Freiburg, Germany;
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.affiliation: Integrin Signalling Laboratory, Cell Biology and Physiology Program, Cell and Developmental Biology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain;
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: del Pozo
authors.affiliation: Department of Pathology, Freiburg University Medical Center, Albert-Ludwigs University, Freiburg, Germany;
authors.forename: Annette
authors.initials: A
authors.lastname: Schmitt-Graeff
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center, Freiburg, Germany;
authors.forename: Justus
authors.initials: J
authors.lastname: Duyster
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN; and.
authors.forename: Keli I
authors.initials: KI
authors.lastname: Hippen
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN; and.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Faculty of Biology, Albert-Ludwigs University, Freiburg, Germany; Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany;
authors.forename: Kristina
authors.initials: K
authors.lastname: Schachtrup
authors.affiliation: Faculty of Biology, Albert-Ludwigs University, Freiburg, Germany; Centre for Biological Signalling Studies BIOSS, Albert-Ludwigs University, Freiburg, Germany.
authors.forename: Susana
authors.initials: S
authors.lastname: Minguet
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center, Freiburg, Germany; Centre for Biological Signalling Studies BIOSS, Albert-Ludwigs University, Freiburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Zeiser
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D002454:Cell Differentiation; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D006086:Graft vs Host Disease / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011446:Prospective Studies; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C495540:CAV1 protein, human; D018106:CD28 Antigens; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell; C402726:Sh2d2a protein, mouse; D016212:Transforming Growth Factor beta
references.citation: Blood. 2014 Oct 16;124(16):2586-95
references.pmid: 25205119
references.citation: Mol Biol Cell. 2000 Jan;11(1):325-37
references.pmid: 10637311
references.citation: J Biol Chem. 2001 Mar 2;276(9):6727-38
references.pmid: 11102446
references.citation: Nat Rev Mol Cell Biol. 2000 Oct;1(1):31-9
references.pmid: 11413487
references.citation: Science. 2001 Sep 28;293(5539):2449-52
references.pmid: 11498544
references.citation: J Biol Chem. 2002 Mar 15;277(11):8771-4
references.pmid: 11805080
references.citation: J Biol Chem. 2002 Nov 1;277(44):41295-8
references.pmid: 12189159
references.citation: Nat Med. 2003 Sep;9(9):1144-50
references.pmid: 12925844
references.citation: Biol Blood Marrow Transplant. 2004 Feb;10(2):91-105
references.pmid: 14750075
references.citation: J Immunol. 2004 May 1;172(9):5149-53
references.pmid: 15100250
references.citation: Oncogene. 2004 Sep 9;23(41):6967-79
references.pmid: 15273741
references.citation: Transplant Proc. 1974 Dec;6(4):367-71
references.pmid: 4155153
references.citation: J Immunol. 1986 May 15;136(10):3543-8
references.pmid: 2871104
references.citation: Nature. 1992 May 14;357(6374):161-4
references.pmid: 1579166
references.citation: FEBS Lett. 1998 May 29;428(3):205-11
references.pmid: 9654135
references.citation: J Mol Biol. 2005 Apr 29;348(2):491-501
references.pmid: 15811383
references.citation: J Cell Biol. 2005 Oct 10;171(1):121-31
references.pmid: 16203859
references.citation: Biochem Biophys Res Commun. 2006 Jan 6;339(1):204-8
references.pmid: 16293224
references.citation: Nat Immunol. 2005 Dec;6(12):1219-27
references.pmid: 16244650
references.citation: Blood. 2006 Jul 1;108(1):390-9
references.pmid: 16522809
references.citation: Immunity. 2007 Jan;26(1):43-54
references.pmid: 17188005
references.citation: Immunol Lett. 2008 Mar 15;116(2):195-202
references.pmid: 18207249
references.citation: FEBS Lett. 2009 Feb 18;583(4):597-606
references.pmid: 19167383
references.citation: Lancet. 2009 May 2;373(9674):1550-61
references.pmid: 19282026
references.citation: J Cell Biol. 2009 May 4;185(3):381-5
references.pmid: 19398762
references.citation: J Exp Med. 2010 Aug 2;207(8):1701-11
references.pmid: 20660617
references.citation: Blood. 2011 Jan 20;117(3):1061-70
references.pmid: 20952687
references.citation: Blood. 2011 Apr 7;117(14):3921-8
references.pmid: 21292771
references.citation: Eur J Immunol. 2011 May;41(5):1242-8
references.pmid: 21469110
references.citation: Sci Transl Med. 2011 May 18;3(83):83ra41
references.pmid: 21593401
references.citation: J Immunol. 2011 Sep 15;187(6):2993-3002
references.pmid: 21849673
references.citation: N Engl J Med. 2011 Dec 1;365(22):2055-66
references.pmid: 22129252
references.citation: Nat Immunol. 2012 Jun;13(6):596-603
references.pmid: 22544392
references.citation: FASEB J. 2012 Nov;26(11):4561-75
references.pmid: 22872677
references.citation: Blood. 2013 Apr 25;121(17):3307-18
references.pmid: 23327924
references.citation: PLoS Biol. 2013 Oct;11(10):e1001674
references.pmid: 24115907
references.citation: FEBS Lett. 2013 Dec 11;587(24):3912-20
references.pmid: 24211445
references.citation: J Immunol. 2013 Dec 15;191(12):6191-9
references.pmid: 24244013
references.citation: Eur J Immunol. 2014 Mar;44(3):785-93
references.pmid: 24307208