title: Key Residues at Third CDR3β Position Impact Structure and Antigen Recognition of Human Invariant NK TCRs.
abstract: The human invariant NK (iNK) TCR is largely composed of the invariant TCR Vα24-Jα18 chain and semivariant TCR Vβ11 chains with variable CDR3β sequences. The direct role of CDR3β in Ag recognition has been studied extensively. Although it was noted that CDR3β can interact with CDR3α, how this interaction might indirectly influence Ag recognition is not fully elucidated. We observed that the third position of Vβ11 CDR3 can encode an Arg or Ser residue as a result of somatic rearrangement. Clonotypic analysis of the two iNK TCR types with a single amino acid substitution revealed that the staining intensity by anti-Vα24 Abs depends on whether Ser or Arg is encoded. When stained with an anti-Vα24-Jα18 Ab, human primary invariant NKT cells could be divided into Vα24 low- and high-intensity subsets, and Arg-encoding TCR Vβ11 chains were more frequently isolated from the Vα24 low-intensity subpopulation compared with the Vα24 high-intensity subpopulation. The Arg/Ser substitution also influenced Ag recognition as determined by CD1d multimer staining and CD1d-restricted functional responses. Importantly, in silico modeling validated that this Ser-to-Arg mutation could alter the structure of the CDR3β loop, as well as the CDR3α loop. Collectively, these results indicate that the Arg/Ser encoded at the third CDR3β residue can effectively modulate the overall structure of, and Ag recognition by, human iNK TCRs.
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, Ontario 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, Ontario M5G 2M9, Canada.|Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Tingxi
authors.initials: T
authors.lastname: Guo
authors.affiliation: Program in Molecular Structure and Function, The Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scally
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, Ontario M5G 2M9, Canada.
authors.forename: Yuki
authors.identifier: 0000-0002-6216-6730
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, Ontario M5G 2M9, Canada.|Department of Immunology, University of Toronto, Toronto, Ontario 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, Ontario M5G 2M9, Canada.|Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Chung-Hsi
authors.initials: CH
authors.lastname: Wang
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, Ontario 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, Ontario 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, Ontario M5G 2M9, Canada.|Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Marcus O
authors.identifier: 0000-0002-9840-7057
authors.initials: MO
authors.lastname: Butler
authors.affiliation: Division of Pediatric Surgery, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.|Department of Surgery, University of Toronto, Toronto, Ontario M5S 1A8, Canada; and.
authors.forename: Priscilla P L
authors.initials: PP
authors.lastname: Chiu
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.|Program in Molecular Structure and Function, The Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada.|Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Julien
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, Ontario M5G 2M9, Canada; naoto.hirano@utoronto.ca.|Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Naoto
authors.identifier: 0000-0001-9070-4754
authors.initials: N
authors.lastname: Hirano
mesh_terms: D000941:Antigens / Q000276:immunology*; D055610:Antigens, CD1d / Q000276:immunology; D022801:Complementarity Determining Regions / Q000737:chemistry; D006801:Humans; D056004:Molecular Dynamics Simulation; D055611:Natural Killer T-Cells / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*
chemical_list: D000941:Antigens; D055610:Antigens, CD1d; C526877:CD1D protein, human; D022801:Complementarity Determining Regions; D011948:Receptors, Antigen, T-Cell