title: Central tolerance spares the private high-avidity CD4(+) T-cell repertoire specific for an islet antigen in NOD mice.
abstract: Although central tolerance induces the deletion of most autoreactive T cells, some autoreactive T cells escape thymic censorship. Whether potentially harmful autoreactive T cells present distinct TCRαβ features remains unclear. Here, we analyzed the TCRαβ repertoire of CD4(+) T cells specific for the S100β protein, an islet antigen associated with type 1 diabetes. We found that diabetes-resistant NOD mice deficient for thymus specific serine protease (TSSP), a protease that impairs class II antigen presentation by thymic stromal cells, were hyporesponsive to the immunodominant S100β1-15 epitope, as compared to wild-type NOD mice, due to intrathymic negative selection. In both TSSP-deficient and wild-type NOD mice, the TCRαβ repertoire of S100β-specific CD4(+) T cells though diverse showed a specific bias for dominant TCRα rearrangements with limited CDR3α diversity. These dominant TCRα chains were public since they were found in all mice. They were of intermediate- to low-avidity. In contrast, high-avidity T cells expressed unique TCRs specific to each individual (private TCRs) and were only found in wild-type NOD mice. Hence, in NOD mice, the autoreactive CD4(+) T-cell compartment has two major components, a dominant and public low-avidity TCRα repertoire and a private high-avidity CD4(+) T-cell repertoire; the latter is deleted by re-enforced negative selection.
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.|INSERM, U1043, Toulouse, France.|CNRS, UMR5282, Toulouse, France.|Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Serre
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.|INSERM, U1043, Toulouse, France.|CNRS, UMR5282, Toulouse, France.|Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Fazilleau
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.|INSERM, U1043, Toulouse, France.|CNRS, UMR5282, Toulouse, France.|Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Guerder
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D061167:Central Tolerance / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D005434:Flow Cytometry; D007515:Islets of Langerhans / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D064568:S100 Calcium Binding Protein beta Subunit / Q000276:immunology*; D012697:Serine Endopeptidases / Q000172:deficiency / Q000276:immunology
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta; D064568:S100 Calcium Binding Protein beta Subunit; C579159:S100b protein, mouse; D012697:Serine Endopeptidases
keywords: Autoimmunity; Avidity; CD4+ T cells; NOD; T-cell tolerance; TCR repertoire