Detection of an autoreactive T-cell population within the polyclonal repertoire that undergoes distinct autoimmune regulator (Aire)-mediated selection

Abstract

The autoimmune regulator (Aire) plays a critical role in central tolerance by promoting the display of tissue-specific antigens in the thymus. To study the influence of Aire on thymic selection in a physiological setting, we used tetramer reagents to detect autoreactive T cells specific for the Aire-dependent tissue-specific antigen interphotoreceptor retinoid-binding protein (IRBP), in the polyclonal repertoire. Two class II tetramer reagents were designed to identify T cells specific for two different peptide epitopes of IRBP. Analyses of the polyclonal T-cell repertoire showed a high frequency of activated T cells specific for both IRBP tetramers in Aire −/− mice, but not in Aire +/+ mice. Surprisingly, although one tetramer-binding T-cell population was efficiently deleted in the thymus in an Aire-dependent manner, the second tetramer-binding population was not deleted and could be detected in both the Aire −/− and Aire +/+ T-cell repertoires. We found that Aire-dependent thymic deletion of IRBP-specific T cells relies on intercellular transfer of IRBP between thymic stroma and bone marrow-derived antigen-presenting cells. Furthermore, our data suggest that Aire-mediated deletion relies not only on thymic expression of IRBP, but also on proper antigen processing and presentation of IRBP by thymic antigen-presenting cells.autoimmunity | uveitis T hymic tolerance mechanisms play an important role in preventing autoimmunity. A key mediator in thymic tolerance is the Autoimmune Regulator (Aire), a transcriptional regulator that is highly expressed in medullary thymic epithelial cells (mTECs) (1). Aire promotes the expression of peripheral tissuespecific self-antigens (TSAs) in mTECs for the purpose of tolerizing self-reactive T cells to these TSAs. Both patients and mice with defects in Aire develop multiorgan autoimmunity, reinforcing the importance of this process in controlling immune tolerance (2). Several organ-specific autoimmune diseases in the Aire-deficient model can be linked to a failure in the appropriate thymic expression of a given TSA under the control of Aire (3-6). Autoimmunity in the eyes of Aire-deficient mice arises as a response against the retina-specific protein interphotoreceptor retinoid binding protein (IRBP) (3). IRBP is expressed in the thymus in an Aire-dependent fashion, and thymic transfer of IRBP-deficient thymi into athymic (nude) WT hosts is sufficient to induce posterior uveitis (3).To date, the detection of Aire-mediated thymic negative selection has relied on the use of T-cell receptor (TCR) transgenic mice (7,8). In these TCR transgenic models, the TCRs are specific for model foreign antigens, and "neo"-self antigen expression is provided by a second transgene where the model antigen is expressed under the control of a tissue-specific promoter that results in mTEC expression. Although such transgenic models have been instructive in demonstrating the potential role of Aire in negative selection, the physiological meaning of these studies is limited by a number of factors, inc...

Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells

“…6E), arguing against general compound-induced toxicity. This conclusion was solidified by the fact that I-BET151 had no detectable effect on selection of an Aire-independent T-cell specificity, A b :IRBP(786-797) (8) (Fig. 6 C and D).…”

“…MHC: PTA-peptide complexes mold the T-cell repertoire by inducing negative selection of self-reactive specificities (6)(7)(8) or by promoting positive selection of regulatory T cells (9,10). By a stillobscure mechanism, Aire-induced MEC-generated peptides are also cross-presented by local dendritic cells (8,10). As a consequence, humans and mice harboring a defective AIRE/Aire locus develop multiorgan autoimmunity (1, 2).…”

What people with Down Syndrome can teach us about cardiopulmonary disease

“…Decreased AIRE protein expression results in an altered programme of downstream gene expression that compromises myeloid immune cell numbers, phenotypes and function [203]. During development, AIRE controls expression of peripheral tissue specific antigens in medullary thymic epithelial cells through which selection of T-cell clones is accomplished [204]. Autoantibodies and mutations in AIRE have been described in Down syndrome with autoimmune polyendocrine syndrome type I [205], leading to thymic hypofunction and primary immunodeficiency [206].…”

Optimal T-cell receptor affinity for inducing autoimmunity

“…However, negative selection is not a perfect process, and a small number of self-reactive T cells are found in the periphery (7). Previous work from our laboratory defined the affinity threshold where negative selection is initiated (1,8).…”