title: Minimal tolerance to a tumor antigen encoded by a cancer-germline gene.
abstract: Central tolerance toward tissue-restricted Ags is considered to rely on ectopic expression in the thymus, which was also observed for tumor Ags encoded by cancer-germline genes. It is unknown whether endogenous expression shapes the T cell repertoire against the latter Ags and explains their weak immunogenicity. We addressed this question using mouse cancer-germline gene P1A, which encodes antigenic peptide P1A(35-43) presented by H-2L(d). We made P1A-knockout (P1A-KO) mice and asked whether their anti-P1A(35-43) immune responses were stronger than those of wild-type mice and whether P1A-KO mice responded to other P1A epitopes, against which wild-type mice were tolerized. We observed that both types of mice mounted similar P1A(35-43)-specific CD8 T cell responses, although the frequency of P1A(35-43)-specific CD8 T cells generated in response to P1A-expressing tumors was slightly higher in P1A-KO mice. This higher reactivity allowed naive P1A-KO mice to reject spontaneously P1A-expressing tumors, which progressed in wild-type mice. TCR-Vβ usage of P1A(35-43)-specific CD8 cells was slightly modified in P1A-KO mice. Peptide P1A(35-43) remained the only P1A epitope recognized by CD8 T cells in both types of mice, which also displayed similar thymic selection of a transgenic TCR recognizing P1A(35-43). These results indicate the existence of a minimal tolerance to an Ag encoded by a cancer-germline gene and suggest that its endogenous expression only slightly affects diversification of the T cell repertoire against this Ag.
authors.affiliation: Ludwig Institute for Cancer Research, Brussels, Belgium.
authors.forename: Ivo J
authors.initials: IJ
authors.lastname: Huijbers
authors.forename: Saïdi M
authors.initials: SM
authors.lastname: Soudja
authors.forename: Catherine
authors.initials: C
authors.lastname: Uyttenhove
authors.forename: Michel
authors.initials: M
authors.lastname: Buferne
authors.forename: Else-Marit
authors.initials: EM
authors.lastname: Inderberg-Suso
authors.forename: Didier
authors.initials: D
authors.lastname: Colau
authors.forename: Luc
authors.initials: L
authors.lastname: Pilotte
authors.forename: Céline G
authors.initials: CG
authors.lastname: Powis de Tenbossche
authors.forename: Patrick
authors.initials: P
authors.lastname: Chomez
authors.forename: Francis
authors.initials: F
authors.lastname: Brasseur
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Schmitt-Verhulst
authors.forename: Benoît J
authors.initials: BJ
authors.lastname: Van den Eynde
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000276:immunology*; D010455:Peptides / Q000235:genetics / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D000939:Epitopes; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta; C507749:cancer-testis antigen P1A, mouse