title: Antigen-specific inhibition of high-avidity T cell target lysis by low-avidity T cells via trogocytosis.
abstract: Current vaccine conditions predominantly elicit low-avidity cytotoxic T lymphocytes (CTLs), which are non-tumor-cytolytic but indistinguishable by tetramer staining or enzyme-linked immunospot from high-avidity CTLs. Using CTL clones of high or low avidity for melanoma antigens, we show that low-avidity CTLs can inhibit tumor lysis by high-avidity CTLs in an antigen-specific manner. This phenomenon operates in vivo: high-avidity CTLs control tumor growth in animals but not in combination with low-avidity CTLs specific for the same antigen. The mechanism involves stripping of specific peptide-major histocompatibility complexes (pMHCs) via trogocytosis by low-avidity melanoma-specific CTLs without degranulation, leading to insufficient levels of specific pMHC on target cell surface to trigger lysis by high-avidity CTLs. As such, peptide repertoire on the cell surface is dynamic and continually shaped by interactions with T cells. These results describe immune regulation by low-avidity T cells and have implications for vaccine design.
authors.affiliation: Department of Cancer Immunotherapeutics & Tumor Immunology (CITI), City of Hope National Medical Center, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
authors.forename: Brile
authors.initials: B
authors.lastname: Chung
authors.affiliation: Department of Medicine, Division of Hematology, Stanford University, 300 Pasteur Dr., Stanford, CA 94305, USA.|Light Microscopy Imaging Core, City of Hope National Medical Center, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
authors.forename: Tor B
authors.initials: TB
authors.lastname: Stuge
authors.affiliation: Department of Cancer Immunotherapeutics & Tumor Immunology (CITI), City of Hope National Medical Center, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Murad
authors.affiliation: Department of Medicine, Division of Bone Marrow Transplantation, Stanford University, 300 Pasteur Dr., Stanford, CA 94305, USA.
authors.forename: Georg
authors.initials: G
authors.lastname: Beilhack
authors.affiliation: Department of Cancer Immunotherapeutics & Tumor Immunology (CITI), City of Hope National Medical Center, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Andersen
authors.affiliation: Department of Cancer Immunotherapeutics & Tumor Immunology (CITI), City of Hope National Medical Center, 1500 E. Duarte Rd, Duarte, CA 91010, USA.|Light Microscopy Imaging Core, City of Hope National Medical Center, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Armstrong
authors.affiliation: Moffitt Cancer Center, University of Southern Florida, 12902 Magnolia Dr, Tampa, FL 33612, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Weber
authors.affiliation: Department of Cancer Immunotherapeutics & Tumor Immunology (CITI), City of Hope National Medical Center, 1500 E. Duarte Rd, Duarte, CA 91010, USA.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Lee
mesh_terms: D000915:Antibody Affinity; D000920:Antibody-Dependent Cell Cytotoxicity; D015234:HLA-A Antigens / Q000276:immunology*; D006801:Humans; D008545:Melanoma / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D015234:HLA-A Antigens
references.citation: J Immunol. 2011 Dec 1;187(11):5733-44
references.pmid: 22039305
references.citation: Nat Med. 2004 Sep;10(9):909-15
references.pmid: 15340416
references.citation: Immunity. 2000 Dec;13(6):829-40
references.pmid: 11163198
references.citation: Immunity. 2005 Mar;22(3):275-84
references.pmid: 15780985
references.citation: PLoS Med. 2004 Nov;1(2):e28
references.pmid: 15578105
references.citation: Nat Med. 2003 Apr;9(4):469-76
references.pmid: 12652294
references.citation: J Exp Med. 2008 Aug 4;205(8):1859-68
references.pmid: 18625745
references.citation: Immunity. 1998 Feb;8(2):167-75
references.pmid: 9491998
references.citation: Biotechnol Prog. 2005 Jul-Aug;21(4):1289-96
references.pmid: 16080713
references.citation: Nat Med. 2003 Nov;9(11):1377-82
references.pmid: 14528297
references.citation: Curr Opin Immunol. 2003 Feb;15(1):120-7
references.pmid: 12495743
references.citation: J Immunol. 2012 Jan 15;188(2):632-40
references.pmid: 22156347
references.citation: Nat Rev Cancer. 2006 Mar;6(3):204-16
references.pmid: 16498443
references.citation: J Immunol. 2012 Nov 15;189(10):4728-39
references.pmid: 23066151
references.citation: Cancer Res. 2008 Mar 15;68(6):2006-13
references.pmid: 18339883
references.citation: J Exp Med. 2000 Oct 16;192(8):1105-13
references.pmid: 11034600
references.citation: Eur J Immunol. 2005 Aug;35(8):2284-94
references.pmid: 16021601
references.citation: Immunity. 1999 Apr;10(4):485-92
references.pmid: 10229191
references.citation: Eur J Immunol. 2000 May;30(5):1458-68
references.pmid: 10820394
references.citation: Biochim Biophys Acta. 2014 Feb;1838(2):557-68
references.pmid: 23860253
references.citation: J Immunol. 2013 Jun 1;190(11):5856-65
references.pmid: 23626012
references.citation: Semin Immunol. 2004 Oct;16(5):323-33
references.pmid: 15528077
references.citation: J Immunol. 2011 May 1;186(9):5039-45
references.pmid: 21505216
references.citation: Nat Immunol. 2002 Jan;3(1):27-32
references.pmid: 11731800
references.citation: J Immunol Methods. 2003 Sep;280(1-2):25-35
references.pmid: 12972185