The nonpolymorphic MHC Qa-1b mediates CD8+ T cell surveillance of antigen-processing defects.
The nonclassical major histocompatibility complex (MHC) Qa-1b accommodates monomorphic leader peptides and functions as a ligand for germ line receptors CD94/NKG2, which are expressed by natural killer cells and CD8+ T cells. We here describe that the conserved peptides are replaced by a novel peptide repertoire of surprising diversity as a result of impairments in the antigen-processing pathway. This novel peptide repertoire represents immunogenic neoantigens for CD8+ T cells, as we found that these Qa-1b-restricted T cells dominantly participated in the response to tumors with processing deficiencies. A surprisingly wide spectrum of target cells, irrespective of transformation status, MHC background, or type of processing deficiency, was recognized by this T cell subset, complying with the conserved nature of Qa-1b. Target cell recognition depended on T cell receptor and Qa-1b interaction, and immunization with identified peptide epitopes demonstrated in vivo priming of CD8+ T cells. Our data reveal that Qa-1b, and most likely its human homologue human leukocyte antigen-E, is important for the defense against processing-deficient cells by displacing the monomorphic leader peptides, which relieves the inhibition through CD94/NKG2A on lymphocytes, and by presenting a novel repertoire of immunogenic peptides, which recruits a subset of cytotoxic CD8+ T cells.
Oliveira
Cláudia C
CC
Department of Clinical Oncology, Leiden University Medical Center, 2333 ZA Leiden, Netherlands.
van Veelen
Peter A
PA
Querido
Bianca
B
de Ru
Arnoud
A
Sluijter
Marjolein
M
Laban
Sandra
S
Drijfhout
Jan W
JW
van der Burg
Sjoerd H
SH
Offringa
Rienk
R
van Hall
Thorbald
T
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D045744:Cell Line, Tumor; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007157:Immunologic Surveillance / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology; D016131:Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000235:genetics / Q000276:immunology; D009369:Neoplasms / Q000235:genetics / Q000276:immunology; D010455:Peptides / Q000235:genetics / Q000276:immunology*
D015395:Histocompatibility Antigens Class I; D051920:NK Cell Lectin-Like Receptor Subfamily D; D010455:Peptides; C032907:Q surface antigens