title: An Essential Role of the Avidity of T-Cell Receptor in Differentiation of Self-Antigen-reactive CD8+ T Cells.
abstract: Many studies demonstrated crucial roles of avidity of T-cell receptor (TCR) in T-cell fate. However, majority of these findings resulted from analysis of non-self-antigen-specific CD8 T cells, and little is known about roles of TCR avidity in the fate of self-antigen-specific CD8 T cells. Wilms tumor gene 1 (WT1) protein is a self-antigen most suitable for addressing this issue because WT1 protein is a highly immunogenic, typical self-antigen. Here, we isolated 2 distinct and functional TCRs, TCR1 and TCR2, from murine WT1 peptide (RMFPNAPYL)-specific cytotoxic T lymphocytes (WT1-CTLs) and generated TCR1-retrogenic (Rg) and TCR2-Rg mice under T and B-cell-deficient and -reconstituted conditions. TCR1-transduced CD8 T (TCR1-T) cells had approximately 2-fold higher avidity to WT1 peptide than TCR2-transduced CD8 T (TCR2-T) cells. Cytokine production profiles and cell surface phenotypes showed that TCR1-T cells were more differentiated than TCR2-T cells under both conditions. Therefore, TCR1-T cells with TCR avidity higher than that of TCR2-T cells are more differentiated compared with TCR2-T cells. Furthermore, TCR1-T cells that developed under T and B-cell-reconstituted conditions displayed cytotoxicity against endogenously WT1-expressing tumor cells, whereas TCR2 T cells that developed under the same conditions did not. Thus, it was demonstrated, for the first time, that TCR avidity played an essential role in differentiation of self-antigen-reactive T cells, through the success of establishment of two distinct WT1-CTLs with a difference in only TCR avidity under the identical genetic background. Present results should provide us with an insight for elucidation of the differentiation mechanisms of self-antigen-reactive T cells, including tumor antigen-reactive T cells.
authors.affiliation: Departments of *Functional Diagnostic Science †Cancer Immunology ‡Cancer Immunotherapy §Respiratory Medicine, Allergy and Rheumatic Disease ∥Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Kondo
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Fujiki
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nakajima
authors.forename: Erika
authors.initials: E
authors.lastname: Yatsukawa
authors.forename: Soyoko
authors.initials: S
authors.lastname: Morimoto
authors.forename: Naoya
authors.initials: N
authors.lastname: Tatsumi
authors.forename: Sumiyuki
authors.initials: S
authors.lastname: Nishida
authors.forename: Jun
authors.initials: J
authors.lastname: Nakata
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Oka
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tsuboi
authors.forename: Naoki
authors.initials: N
authors.lastname: Hosen
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Oji
authors.forename: Haruo
authors.initials: H
authors.lastname: Sugiyama
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D002460:Cell Line; D003001:Cloning, Molecular; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic; D025721:WT1 Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D001324:Autoantigens; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D025721:WT1 Proteins