title: Surprisingly minor influence of TRAV11 (Valpha14) polymorphism on NK T-receptor mCD1/alpha-galactosylceramide binding kinetics.
abstract: Defects in natural killer T (NK T) cell function and of interleukin-4 -production in SJL and NOD mice have been linked to susceptibility to autoimmune disease. As SJL and NOD mice both carry the T-cell receptor (TCR) alpha-chain locus "c" (Tcra(c)) haplotype, found in few other strains, we have attempted to determine the influence of Tcra polymorphism on NK T-cell recognition of ligand, selection, and immune responses. The majority of NK T cells use an "invariant" TRAV11J15 (previously called AV14J18 or Valpha14 Jalpha281) alpha- chain paired with either TRBV13-2, BV29, or BV1 to recognize ligands presented by mCD1 molecules, including the glycolipid alpha-galactosylceramide (alpha-GalCer). Sequencing of TRAV11 from the mouse strains B10.A (encoding the Tcra(b) haplotype), B10.A- Tcra(c), and NOD (Tcra(c)) shows that Tcra(c) has a single TRAV11 gene (TRAV11*01) and that Tcra(b) has a single expressed gene (TRAV11*02), plus a closely related pseudogene. There is no apparent difference in alpha-chain J-region usage or in the CDR3alpha sequence at the TRAV11-J15 junction between the haplotypes in TRAV11-bearing NK T cells. Using Biacore and tetramer-binding and decay assays, we have determined that the interaction between Tcra(c) TRAV11*01 NK T TCR and the mCD1/alpha-GalCer complex is slightly weaker than that of Tcra(b) (i.e., TRAV11*02) NK T TCR. These differences are minor compared with differences between agonist and antagonist ligands in other TCR systems, suggesting that it is unlikely that TCR polymorphism explains the defect in NK T cells in the autoimmune mouse strains.
authors.affiliation: IMM1, Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Bee-Cheng
authors.initials: BC
authors.lastname: Sim
authors.forename: Kaisa
authors.initials: K
authors.lastname: Holmberg
authors.forename: Stephane
authors.initials: S
authors.lastname: Sidobre
authors.forename: Olga
authors.initials: O
authors.lastname: Naidenko
authors.forename: Nathalie
authors.initials: N
authors.lastname: Niederberger
authors.forename: Shane D
authors.initials: SD
authors.lastname: Marine
authors.forename: Mitchell
authors.initials: M
authors.lastname: Kronenberg
authors.forename: Nicholas R J
authors.initials: NR
authors.lastname: Gascoigne
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020296:Animals, Congenic; D018949:Antigens, CD1 / Q000737:chemistry / Q000378:metabolism*; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D005699:Galactosylceramides / Q000378:metabolism*; D019673:Genes, T-Cell Receptor alpha; D006239:Haplotypes; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics* / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
chemical_list: D018949:Antigens, CD1; D005699:Galactosylceramides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D004247:DNA