title: A broad range of self-reactivity drives thymic regulatory T cell selection to limit responses to self.
abstract: The degree of T cell self-reactivity considered dangerous by the immune system, thereby requiring thymic selection processes to prevent autoimmunity, is unknown. Here, we analyzed a panel of T cell receptors (TCRs) with a broad range of reactivity to ovalbumin (OVA(323-339)) in the rat insulin promoter (RIP)-mOVA self-antigen model for their ability to trigger thymic self-tolerance mechanisms. Thymic regulatory T (Treg) cell generation in vivo was directly correlated with in vitro TCR reactivity to OVA-peptide in a broad ~1,000-fold range. Interestingly, higher TCR affinity was associated with a larger Treg cell developmental "niche" size, even though the amount of antigen should remain constant. The TCR-reactivity threshold to elicit thymic negative selection and peripheral T cell responses was ~100-fold higher than that of Treg cell differentiation. Thus, these data suggest that the broad range of self-reactivity that elicits thymic Treg cell generation is tuned to secure peripheral tolerance to self.
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Hyang-Mi
authors.initials: HM
authors.lastname: Lee
authors.forename: Jhoanne L
authors.initials: JL
authors.lastname: Bautista
authors.forename: James
authors.initials: J
authors.lastname: Scott-Browne
authors.forename: James F
authors.initials: JF
authors.lastname: Mohan
authors.forename: Chyi-Song
authors.initials: CS
authors.lastname: Hsieh
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000737:chemistry / Q000276:immunology; D010455:Peptides / Q000276:immunology; D061166:Peripheral Tolerance / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D017634:Self Tolerance / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism
chemical_list: D001324:Autoantigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D010047:Ovalbumin