Diversity of TCRs on Natural Foxp3+ T Cells in Mice Lacking <i>Aire</i> Expression

Daniely, Danielle; Kern, Joanna; Cebula, Anna; Ignatowicz, Leszek

doi:10.4049/jimmunol.0903609

Cited by 31 publications

(28 citation statements)

References 34 publications

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“…Extensive analysis of TCR Vα and Vβ use and CDR3 length distribution showed that the TCR repertoires of WT and AIRE°C D8 + CD28 low Treg are very diverse and very similar. This result parallels the finding of apparently similar TCR repertoires of WT versus AIRE°CD4 + Foxp3 + Treg (33). However, using immunoscope analysis a very reproducible difference was observed, showing that the TCR repertoires of CD8 + CD28 low cells from WT versus AIRE°mice are not identical.…”

Section: Discussionsupporting

confidence: 72%

“…In AIRE°mice, marginally reduced numbers of CD4 + Foxp3 + Treg may develop. However, molecular analysis of the TCR repertoire of WT and AIRE°CD4 + Foxp3 + Treg failed to detect any difference, and these cells have unaltered in vitro and in vivo suppressive activity (20,21,30,32,33). In APECED patients, decreased expression of Foxp3 and impaired suppressive function of Treg were observed (34).…”

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confidence: 99%

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Autoimmune regulator (AIRE)-deficient CD8⁺CD28^lowregulatory T lymphocytes fail to control experimental colitis

Pomié

Vicente

Vuddamalay

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the gene encoding the transcription factor autoimmune regulator (AIRE) are responsible for autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome. AIRE directs expression of tissue-restricted antigens in the thymic medulla and in lymph node stromal cells and thereby substantially contributes to induction of immunological tolerance to self-antigens. Data from experimental mouse models showed that AIRE deficiency leads to impaired deletion of autospecific T-cell precursors. However, a potential role for AIRE in the function of regulatory T-cell populations, which are known to play a central role in prevention of immunopathology, has remained elusive. Regulatory T cells of CD8 + CD28 low phenotype efficiently control immune responses in experimental autoimmune and colitis models in mice. Here we show that CD8 + CD28 low regulatory T lymphocytes from AIRE-deficient mice are transcriptionally and phenotypically normal and exert efficient suppression of in vitro immune responses, but completely fail to prevent experimental colitis in vivo. Our data therefore demonstrate that AIRE plays an important role in the in vivo function of a naturally occurring regulatory T-cell population.

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Section: Discussionsupporting

confidence: 72%

mentioning

confidence: 99%

Autoimmune regulator (AIRE)-deficient CD8⁺CD28^lowregulatory T lymphocytes fail to control experimental colitis

Pomié

Vicente

Vuddamalay

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Despite the importance of Aire in facilitating negative selection (Liston et al, 2003), its role in Treg cell development is controversial. One TCR repertoire analysis suggests that Aire has little effect on Treg cell selection (Daniely et al, 2010), which is consistent with the observation that Aire -deficient mice have normal Treg cell numbers (Anderson et al, 2005). However, these findings are contrary to a recent study showing that Aire is required for thymic Treg cell selection of two TCR transgenic lines specific to endogenous prostate-specific antigen (Malchow et al, 2013), as well as studies of TCR:cognate antigen transgenic models.…”

Section: Introductionsupporting

confidence: 77%

“…The role of Aire in Treg cell selection has been controversial (Anderson et al, 2005; Daniely et al, 2010; Malchow et al, 2013). Therefore, we assessed the TCR repertoire of Aire∼ / ∼ mice with a TClip transgene (Figure S5A-C).…”

Section: Resultsmentioning

confidence: 99%

Distinct Contributions of Aire and Antigen-Presenting-Cell Subsets to the Generation of Self-Tolerance in the Thymus

et al. 2014

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Summary The contribution of thymic antigen presenting cell (APC) subsets in selecting a selftolerant T cell population remains unclear. We show that bone marrow (BM) APCs and medullary thymic epithelial cells (mTECs) played non-overlapping roles in shaping the T cell receptor (TCR) repertoire by deletion and regulatory T (Treg) cell selection of distinct TCRs. Aire, which induces tissue-specific-antigen expression in mTECs, affected the TCR repertoire in a manner distinct from mTEC presentation. Approximately half of Aire-dependent deletion or Treg cell selection utilized a pathway dependent on antigen presentation by BM APCs. Batf3-dependent CD8α+ dendritic cells (DCs) were the crucial BM APC for Treg cell selection via this pathway, showing enhanced ability to present antigens from stromal cells. These results demonstrate the division of function between thymic APCs in shaping the self-tolerant TCR repertoire, and reveal an unappreciated cooperation between mTECs and CD8α+ DCs for presentation of Aire-induced self-antigens to developing thymocytes.

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“…Other studies concluded that Treg cells are rather non-self-specific, in line with their role in antifungal, -viral, or -bacterial immune responses [30][31][32]. In particular, TCR sequencing studies on TCR mini mice suggested that Treg cells with thymus origin might recognize non-self-antigens at high frequency [18,33] and that their thymic selection is not controlled by Aire-dependent tissue-specific (self) antigens [34]. We believe that these opposite views can be reconciled by taking into account that there are distinct subpopulations of Treg cells.…”

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confidence: 91%

TCR sequences and tissue distribution discriminate the subsets of naïve and activated/memory Treg cells in mice

et al. 2015

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Analyses of the regulatory T (TregEur. J. Immunol. 2015Immunol. . 45: 1524Immunol. -1534 Molecular immunology 1525 been described so far: natural Treg cells, which arise in the thymus [7], renamed tTreg cells [8], and induced Treg cells, which differentiate from naïve CD4 + precursors in the periphery [9,10].Recently, the wide range of Treg-cell functional properties has been associated with phenotypical heterogeneity, such as their homing [6] and their activation status, that defines their anatomical location and homeostasis [11][12][13][14]. How Treg-cell antigen specificity relates to these functions remains poorly understood. Indeed, while Treg-cell activation is largely antigen-specific, the nature of their recognized antigens is still unclear. Theoretically, protecting normal tissues with Treg cells could be handled by a very restricted set of Treg cells specifically recognizing ubiquitously expressed self-antigens. However, many studies concluded that the Treg TCR repertoire is as complex as the effector T (Teff) cell repertoire [15][16][17][18], suggesting that the set of self-antigens recognized by Treg cells is quite complex and may be different at distinct anatomical location [11,19]. Deciphering the nature of the Treg-cell repertoire is of utmost importance for the understanding of their biology.Indeed, it is believed that during thymocyte differentiation, the affinity of the interaction between the TCRs and antigens presented onto thymic antigen-presenting cells (APCs) determines the fate of each cell [20]. The current paradigm is that of a mostly instructive process in which signaling from high-affinity TCRs, likely self-antigen specific, leads to negative selection except for a fraction of cells that will be selected to become Treg cells [21]. Hierarchical clustering of perturbation scores (Fig. 2B, top) discriminates Teff samples from nTreg-cell and amTreg-cell samples. Treg-cell subsets are dispersed into two clusters (I and II), while all but two Teff-cell samples are found in cluster III. Principal component analysis (PCA) projection (Fig. 2B, bottom) depicts this overlap between amTreg-cell and nTreg-cell repertoires.We then focused on amTreg-cell and nTreg-cell samples only and used their perturbation scores against Teff-cell samples to perform a hierarchical clustering according to their LNs localization. Hierarchical clustering leads to two clusters (I and II) (Fig. 2C, top) discriminating deep LNs samples in cluster I, while cluster II mainly gathers superficial LNs samples. Noteworthy, the first component of the PCA projection (PC1), which captures 43% of variability, mainly correlates with sample localization (Fig. 2C, bottom), indicating an increased gradation of perturbation from superficial LN nTreg cells to deep LN amTreg cells.Altogether, hierarchical clustering and PCA separated the different population repertoires, with amTreg cells repertoire being the more perturbed and more distant from that of Teff cells. Furthermore, the PCA projection also showed a rather high interindivi...

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Diversity of TCRs on Natural Foxp3+ T Cells in Mice Lacking Aire Expression

Cited by 31 publications

References 34 publications

Autoimmune regulator (AIRE)-deficient CD8⁺CD28^lowregulatory T lymphocytes fail to control experimental colitis

Autoimmune regulator (AIRE)-deficient CD8⁺CD28^lowregulatory T lymphocytes fail to control experimental colitis

Distinct Contributions of Aire and Antigen-Presenting-Cell Subsets to the Generation of Self-Tolerance in the Thymus

TCR sequences and tissue distribution discriminate the subsets of naïve and activated/memory Treg cells in mice

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Diversity of TCRs on Natural Foxp3+ T Cells in Mice Lacking Aire Expression

Cited by 31 publications

References 34 publications

Autoimmune regulator (AIRE)-deficient CD8+CD28lowregulatory T lymphocytes fail to control experimental colitis

Autoimmune regulator (AIRE)-deficient CD8+CD28lowregulatory T lymphocytes fail to control experimental colitis

Distinct Contributions of Aire and Antigen-Presenting-Cell Subsets to the Generation of Self-Tolerance in the Thymus

TCR sequences and tissue distribution discriminate the subsets of naïve and activated/memory Treg cells in mice

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Autoimmune regulator (AIRE)-deficient CD8⁺CD28^lowregulatory T lymphocytes fail to control experimental colitis

Autoimmune regulator (AIRE)-deficient CD8⁺CD28^lowregulatory T lymphocytes fail to control experimental colitis