AIRE expands: new roles in immune tolerance and beyond

Anderson, Mark S.; Su, Maureen A.

doi:10.1038/nri.2016.9

Cited by 227 publications

(221 citation statements)

References 96 publications

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“…Some tumor-associated antigens, such as tyrosinase-related protein 1 (TYRP1, also known as TRP1), are expressed in medullary thymic epithelial cells 18 . In addition, tumors can escape anti-tumor T cell responses by decreasing their expression of tumor-associated antigens and/or MHC molecules; by secreting immunosuppressive soluble factors (vascular endothelial growth factor, stromalcell-derived factor, interleukin 10, interleukin 6, transforming growth factor-β, adenosine, and prostaglandins); and/or by engaging immune checkpoints (CTLA-4, PD-1, Tim-3, and LAG-3) that suppress anti-tumor activity.…”

Section: Barriers To Immune Recognition Of Tumorsmentioning

confidence: 99%

Is autoimmunity the Achilles' heel of cancer immunotherapy?

June

Warshauer

Bluestone

2017

Nat Med

383

308

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Section: Barriers To Immune Recognition Of Tumorsmentioning

confidence: 99%

Is autoimmunity the Achilles' heel of cancer immunotherapy?

June

Warshauer

Bluestone

2017

Nat Med

383

308

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“…An essential component of the negative selection process is the display of self-antigens by medullary thymic epithelial cells (mTECs) to developing T cells. This is coordinated by the Autoimmune Regulator (AIRE) gene that initiates the expression of a wide array of tissuespecific self-antigens, creating an "immunological selfshadow" in the thymus (29). Recently, it was suggested that AIRE expressing mTECs could also promote the thymic development of some clones of self-tolerant Treg (29).…”

Section: General Overview Of T-cell Reconstitution After Allohsctmentioning

confidence: 99%

Reconstitution of adaptive immunity after umbilical cord blood transplantation: impact on infectious complications

Servais

Hannon

Latour

et al. 2017

Stem Cell Investig.

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In comparison with allogeneic stem cell transplantation (alloHSCT) with other stem cell sources, umbilical cord blood transplantation (UCBT) was traditionally associated with increased risk of infections, particularly during the first 3 months after transplantation. Longitudinal studies of immune monitoring reported peculiar patterns of T-and B-cell recovery in the peripheral blood of UCB recipients during the first months post-transplantation. Overall, current data suggest delayed reconstitution of naive and memory CD4+ and CD8 + T-cell pools after UCBT. This is particularly true for adult recipients and for patients who received in vivo T-cell depleting approaches before the transplantation. Such delayed T-cell recovery may increase susceptibility of UCB recipients for developing opportunistic infections and viral reactivations.Regarding B-cell recovery, UCBT was associated with accelerated B-lymphopoiesis. Recent studies also reported evidence for faster functional memory B-cell recovery in UCB recipients. In this article, we briefly review T-and B-cell reconstitution after alloHSCT, with emphasis on peculiarities observed after UCBT.We further put these data in lines with risks of infections after UCBT.

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“…Proof of principle for the latter concept has been established by augmentation of antitumor immunity through transient blockade of AIRE function in adult mice (1). These effects would ideally be limited to mTECs in order to prevent unwanted side effects of sex hormone therapy.…”

Section: Clinical Implications Of Estrogen-mediated Aire Regulationmentioning

confidence: 99%

“…Such an approach has identified critical immuneregulatory genes, such as the autoimmune regulator (AIRE), which encodes a nuclear protein that functions as a key regulator of thymic central tolerance (reviewed in ref. 1). AIRE enforces self tolerance by promoting the promiscuous expression of tissue self-antigens (TSAs) within medullary thymic epithelial cells (mTECs), a nonhematopoietic, stromal cell population (Figure 1A).…”

mentioning

confidence: 99%

Estrogen turns down “the AIRE”

Bakhru¹,

Su²

2016

Journal of Clinical Investigation

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C o m m e n t a r yAutoimmune disease: sex-dependent differencesThe incidence of autoimmune disease is increasing worldwide; therefore, the need to understand the basis of autoimmunity has taken on a new urgency. Progress in identifying genetic contributors to autoimmunity has been made through the study of monogenic autoimmune diseases. Such an approach has identified critical immuneregulatory genes, such as the autoimmune regulator (AIRE), which encodes a nuclear protein that functions as a key regulator of thymic central tolerance (reviewed in ref. 1). AIRE enforces self tolerance by promoting the promiscuous expression of tissue self-antigens (TSAs) within medullary thymic epithelial cells (mTECs), a nonhematopoietic, stromal cell population (Figure 1A). Presentation of these TSAs within the thymus results in negative selection of bone marrow-derived T cells, which recognize these TSAs with high affinity. In addition to eliminating autoreactive T cell clones within the thymus, AIRE also maintains self tolerance by diverting autoreactive T cells into the Treg lineage. AIRE is important for preventing autoimmune disease, as individuals with a complete loss of AIRE function develop the multiorgan autoimmune disease autoimmune polyendocrinopathy syndrome type 1 (APS1, which is also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy [APECED]). While genetics are a major factor that determines autoimmune disease predisposition, it is clear that sex also plays a defining role in disease development. The incidence of autoimmunity is skewed toward females for many autoimmune diseases, including Sjögren's disease, systemic lupus erythematosus (SLE), and autoimmune thyroid disease (reviewed in ref. 2). Remarkably, over 80% of those affected with these conditions are female, illustrating the strong influence of sex in disease predisposition. Multiple factors likely underlie this sex bias, including the distinct sex hormone profiles in females versus males. Accumulating evidence suggests that male androgen hormones are immune suppressive, while female estrogen hormones are immune activating. For instance, androgen increases the differentiation of immunoregulatory CD4+ T cells (3), whereas estrogen enhances survival of T cells in patients with autoimmunity (4). Thus, there is a plethora of evidence that sex hormones directly modulate T cells in the periphery.Early clues that sex hormones may also modulate thymic stromal populations, such as mTECs, came from elegant studies that utilized bone marrow chimeras (5, 6). These studies showed that thymic epithelial cells express estrogen receptor (ER) and androgen receptor (AR) and that expression of these hormone receptors in the stromal compartment is required for altering bone marrow-derived T cell subsets in the thymus (5, 6). In this issue, Dragin et al. confirm that sex hormones indeed act on receptors on thymic stromal cells to impinge upon T cell development within the thymus. Furthermore, this study demonstrates that sex hormones regulate AIRE expre...

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AIRE expands: new roles in immune tolerance and beyond

Cited by 227 publications

References 96 publications

Is autoimmunity the Achilles' heel of cancer immunotherapy?

Is autoimmunity the Achilles' heel of cancer immunotherapy?

Reconstitution of adaptive immunity after umbilical cord blood transplantation: impact on infectious complications

Estrogen turns down “the AIRE”

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