Human Peripheral Lymphoid Tissues Contain Autoimmune Regulator-Expressing Dendritic Cells

Department of Pathology, University of Brescia, P.le Spedali Civili 1, 25123, Brescia, Italy.
American Journal Of Pathology (Impact Factor: 4.59). 03/2010; 176(3):1104-12. DOI: 10.2353/ajpath.2010.090956
Source: PubMed

ABSTRACT Autoimmune regulator (AIRE) modulates the expression of tissue-restricted antigens (TSAs) and promotes central tolerance in the thymus. However, few autoreactive T cells escape negative selection and reach the periphery, where peripheral tolerance is required to avoid autoimmunity. Murine lymph nodes (LNs) have been shown to contain "stromal" cells expressing AIRE and TSAs. Here we report the occurrence of AIRE-expressing cells in human peripheral lymphoid tissues, including LNs, tonsils, and gut-associated lymphoid tissue, with the exception of the spleen. Notably, AIRE+ cells are absent in fetal LNs and, in postnatal life, they are more numerous in abdominal than in superficial LNs, thus suggesting that their development in periphery may depend on instructive signals from microenvironment and antigen challenge. Extrathymic AIRE+ cells show a dendritic morphology, consistently express human leukocyte antigen-DR (HLADR) and fascin, and are largely positive for CD11c and S100 and for the dendritic cell-activation markers CD40, CD83, DC-LAMP/CD208, and CCR7. Lymphoid, myelomonocytic, mesenchymal, and epithelial cell lineage markers are negative. The HLADRhigh/AIRE+ cell fraction isolated from mesenteric LNs expressed TSAs (insulin, CYP17A1, and CYP21A2), as well as molecules associated with tolerogenic functions, such as interleukin-10 and indoleamine 2,3-dioxygenase. Data indicate that AIRE+ cells in human peripheral lymphoid tissues correspond to a subset of activated interdigitating dendritic cells expressing TSAs and the tolerogenic molecules indoleamine 2,3-dioxygenase and interleukin-10, suggestive of a potential tolerogenic function.

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Available from: Anna Villa, Dec 23, 2013
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    • "Investigations into Aire expression in mice have also identified Aire transcripts in secondary lymphoid organs, but detection of Aire protein in these tissues has been variable (Anderson et al., 2002; Halonen et al., 2001; Heino et al., 2000; Hubert et al., 2008). Also, the type of cell expressing Aire in the periphery has been controversial, with groups reporting Aire in both the hematopoietic and stromal lineages (Fletcher et al., 2010; Gardner et al., 2008; Poliani et al., 2010). Previously, we showed that eTACs express high amounts of major histocompatibility complex class II (MHC II) and relevant Immunity 39, 1–13, September 19, 2013 ª2013 Elsevier Inc. 1 Please cite this article in press as: Gardner et al., Extrathymic Aire-Expressing Cells Are a Distinct Bone Marrow-Derived Population that Induce Functional Inactivation of CD4 + T Cells, Immunity (2013), antigen-processing machinery, but lack the high expression of CD80 and CD86 that characterizes other antigen-presenting cell (APC) populations (Gardner et al., 2008). "
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    ABSTRACT: The autoimmune regulator (Aire) is essential for prevention of autoimmunity; its role is best understood in the thymus, where it promotes self-tolerance through tissue-specific antigen (TSA) expression. Recently, extrathymic Aire-expressing cells (eTACs) have been described in murine secondary lymphoid organs, but the identity of such cells and their role in immune tolerance remains unclear. Here we have shown that eTACs are a discrete major histocompatibility complex class II (MHC II)(hi), CD80(lo), CD86(lo), epithelial cell adhesion molecule (EpCAM)(hi), CD45(lo) bone marrow-derived peripheral antigen-presenting cell (APC) population. We also have demonstrated that eTACs can functionally inactivate CD4(+) T cells through a mechanism that does not require regulatory T cells (Treg) and is resistant to innate inflammatory stimuli. Together, these findings further define eTACs as a distinct tolerogenic cell population in secondary lymphoid organs.
    Immunity 08/2013; 39(3). DOI:10.1016/j.immuni.2013.08.005 · 21.56 Impact Factor
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    • "This is in line with data showing AIRE expression in CD11c þ cells in human lymph nodes. However, the exact DC subset corresponding to the murine 33D1 þ splenic DCs remains to be characterised [31]. Thus, we conclude that AIRE is expressed specifically in the 33D1 þ mDC population in mice and we find evidence for its expression in the same DC lineage in humans. "
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    ABSTRACT: Autoimmune polyendocrine syndrome Type I (APS I) results in multiple endocrine organ destruction and is caused by mutations in the Autoimmune regulator gene (AIRE). In the thymic stroma, cells expressing the AIRE gene dictate T cell education and central tolerance. Although this function is the most studied, AIRE is also expressed in the periphery in DCs and stromal cells. Still, how AIRE regulated transcription modifies cell behaviour in the periphery is largely unknown. Here we show that AIRE is specifically expressed by 33D1(+) DCs and dictates the fate of antibody secreting cell movement within the spleen. We also found that AIRE expressing 33D1(+) DCs expresses self-antigens as exemplified by the hallmark gene insulin. Also, as evidence for a regulatory function, absence of Aire in 33D1(+) DCs led to reduced levels of the chemokine CXCL12 and increased co-stimulatory properties. This resulted in altered activation and recruitment of T-follicular helper cells and germinal centre B cells. The altered balance leads to a change of the early response to a T cell-dependent antigen in Aire(-/-) mice. These findings add to the understanding of how specific DC subtypes regulate the early responses during T cell-dependent antibody responses within the spleen and further define the role of AIRE in the periphery as regulator of self-antigen expression and lymphocyte migration.
    Journal of Autoimmunity 12/2012; 42. DOI:10.1016/j.jaut.2012.11.004 · 8.41 Impact Factor
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    • "Interestingly , it was observed that DC maturation is paralleled by increasing AIRE levels and ordinary up-regulation of several genes [14]. Later, Poliani et al. detected AIRE expression in frozen samples of lymph nodes and gut-associated lymphoid tissue (GALT) from adult subjects, while the fetal samples were negative: the cells responsible for such positivity expressed surface markers typical of mature DCs [18] "
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    ABSTRACT: The autoimmune polyendocrine syndrome type 1 (APS-1) is a monogenic disease due to pathogenic variants occurring in the autoimmune regulator (AIRE) gene. Its related protein, AIRE, activates the transcription of genes encoding for tissue-specific antigens (TsAgs) in a subset of medullary thymic epithelial cells: the presentation of TsAgs to the maturating thymocytes induces the apoptosis of the autoreactive clones and constitutes the main form of central tolerance. Dysregulation of thymic AIRE expression in genetically transmitted and acquired diseases other than APS-1 may contribute to further forms of autoimmunity. As AIRE and its murine homolog are also expressed in the secondary lymphoid organs, the extent and relevance of AIRE participation in the mechanisms of peripheral tolerance need to be thoroughly defined.
    Clinical and Developmental Immunology 10/2012; 2012:207403. DOI:10.1155/2012/207403 · 2.93 Impact Factor
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