title: CD4(+) and CD8(+) TCRβ repertoires possess different potentials to generate extraordinarily high-avidity T cells.
abstract: Recent high throughput sequencing analysis has revealed that the TCRβ repertoire is largely different between CD8(+) and CD4(+) T cells. Here, we show that the transduction of SIG35α, the public chain-centric HLA-A*02:01(A2)/MART127-35 TCRα hemichain, conferred A2/MART127-35 reactivity to a substantial subset of both CD8(+) and CD4(+) T cells regardless of their HLA-A2 positivity. T cells individually reconstituted with SIG35α and different A2/MART127-35 TCRβ genes isolated from CD4(+) or CD8(+) T cells exhibited a wide range of avidity. Surprisingly, approximately half of the A2/MART127-35 TCRs derived from CD4(+) T cells, but none from CD8(+) T cells, were stained by A2/MART127-35 monomer and possessed broader cross-reactivity. Our results suggest that the differences in the primary structure of peripheral CD4(+) and CD8(+) TCRβ repertoire indeed result in the differences in their ability to form extraordinarily high avidity T cells which would otherwise have been deleted by central tolerance.
authors.affiliation: Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: Munehide
authors.initials: M
authors.lastname: Nakatsugawa
authors.affiliation: Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: Muhammed A
authors.initials: MA
authors.lastname: Rahman
authors.affiliation: Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yamashita
authors.affiliation: Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Ochi
authors.affiliation: Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.|Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Piotr
authors.initials: P
authors.lastname: Wnuk
authors.affiliation: Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.|Takara Bio, Inc., Kusatsu, Shiga 525-0058, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: Kenji
authors.initials: K
authors.lastname: Chamoto
authors.affiliation: Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kagoya
authors.affiliation: Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Saso
authors.affiliation: Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.|Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Tingxi
authors.initials: T
authors.lastname: Guo
authors.affiliation: Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.|Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Anczurowski
authors.affiliation: Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.|Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Marcus O
authors.initials: MO
authors.lastname: Butler
authors.affiliation: Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.|Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Naoto
authors.initials: N
authors.lastname: Hirano
mesh_terms: D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D003429:Cross Reactions; D015870:Gene Expression; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D058965:MART-1 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D061251:Primary Cell Culture; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D014161:Transduction, Genetic
chemical_list: C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D058965:MART-1 Antigen; C548667:MLANA protein, human; D016693:Receptors, Antigen, T-Cell, alpha-beta