title: Effective functional maturation of invariant natural killer T cells is constrained by negative selection and T-cell antigen receptor affinity.
abstract: The self-reactivity of their T-cell antigen receptor (TCR) is thought to contribute to the development of immune regulatory cells, such as invariant NK T cells (iNKT). In the mouse, iNKT cells express TCRs composed of a unique Vα14-Jα18 rearrangement and recognize lipid antigens presented by CD1d molecules. We created mice expressing a transgenic TCR-β chain that confers high affinity for self-lipid/CD1d complexes when randomly paired with the mouse iNKT Vα14-Jα18 rearrangement to study their development. We show that although iNKT cells undergo agonist selection, their development is also shaped by negative selection in vivo. In addition, iNKT cells that avoid negative selection in these mice express natural sequence variants of the canonical TCR-α and decreased affinity for self/CD1d. However, limiting the affinity of the iNKT TCRs for "self" leads to inefficient Egr2 induction, poor expression of the iNKT lineage-specific zinc-finger transcription factor PLZF, inadequate proliferation of iNKT cell precursors, defects in trafficking, and impaired effector functions. Thus, proper development of fully functional iNKT cells is constrained by a limited range of TCR affinity that plays a key role in triggering the iNKT cell-differentiation pathway. These results provide a direct link between the affinity of the TCR expressed by T-cell precursors for self-antigens and the proper development of a unique population of lymphocytes essential to immune responses.
authors.affiliation: Integrated Department of Immunology, National Jewish Health and University of Colorado School of Medicine, Denver, CO 80206.
authors.forename: Romain
authors.initials: R
authors.lastname: Bedel
authors.forename: Richard
authors.initials: R
authors.lastname: Berry
authors.forename: Thierry
authors.initials: T
authors.lastname: Mallevaey
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Matsuda
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhang
authors.forename: Dale I
authors.initials: DI
authors.lastname: Godfrey
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.forename: John W
authors.initials: JW
authors.lastname: Kappler
authors.forename: Philippa
authors.initials: P
authors.lastname: Marrack
authors.forename: Laurent
authors.initials: L
authors.lastname: Gapin
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000737:chemistry; D002454:Cell Differentiation; D051767:Early Growth Response Protein 2 / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D007107:Immune System; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D055611:Natural Killer T-Cells / Q000166:cytology* / Q000276:immunology; D011401:Promoter Regions, Genetic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics; D020349:Surface Plasmon Resonance; D060168:Thymocytes / Q000166:cytology; D013997:Time Factors
chemical_list: D055610:Antigens, CD1d; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta
keywords: deletion; thymus