title: TCR affinity and tolerance mechanisms converge to shape T cell diabetogenic potential.
abstract: Autoreactive T cells infiltrating the target organ can possess a broad TCR affinity range. However, the extent to which such biophysical parameters contribute to T cell pathogenic potential remains unclear. In this study, we selected eight InsB9-23-specific TCRs cloned from CD4(+) islet-infiltrating T cells that possessed a relatively broad range of TCR affinity to generate NOD TCR retrogenic mice. These TCRs exhibited a range of two-dimensional affinities (∼ 10(-4)-10(-3) μm(4)) that correlated with functional readouts and responsiveness to activation in vivo. Surprisingly, both higher and lower affinity TCRs could mediate potent insulitis and autoimmune diabetes, suggesting that TCR affinity does not exclusively dictate or correlate with diabetogenic potential. Both central and peripheral tolerance mechanisms selectively impinge on the diabetogenic potential of high-affinity TCRs, mitigating their pathogenicity. Thus, TCR affinity and multiple tolerance mechanisms converge to shape and broaden the diabetogenic T cell repertoire, potentially complicating efforts to induce broad, long-term tolerance.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Maria
authors.initials: M
authors.lastname: Bettini
authors.affiliation: Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322;
authors.forename: Lori
authors.initials: L
authors.lastname: Blanchfield
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Ashley
authors.initials: A
authors.lastname: Castellaw
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Qianxia
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO 80045;
authors.forename: Maki
authors.initials: M
authors.lastname: Nakayama
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105; and.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Smeltzer
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105; and.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55414.
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Hogquist
authors.affiliation: Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322;
authors.forename: Brian D
authors.initials: BD
authors.lastname: Evavold
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105; vignali.lab@stjude.org.
authors.forename: Dario A A
authors.initials: DA
authors.lastname: Vignali
mesh_terms: D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000379:methods; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000276:immunology*; D007328:Insulin / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation
chemical_list: D018984:Epitopes, T-Lymphocyte; C561967:Ins2 protein, mouse; D007328:Insulin; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell