In the small intestine, type 2 responses are regulated by a signaling circuit that involves tuft cells and group 2 innate lymphoid cells (ILC2s). Here, we identified the microbial metabolite ...succinate as an activating ligand for small intestinal (SI) tuft cells. Sequencing analyses of tuft cells isolated from the small intestine, gall bladder, colon, thymus, and trachea revealed that expression of tuft cell chemosensory receptors is tissue specific. SI tuft cells expressed the succinate receptor (SUCNR1), and providing succinate in drinking water was sufficient to induce a multifaceted type 2 immune response via the tuft-ILC2 circuit. The helminth Nippostrongylus brasiliensis and a tritrichomonad protist both secreted succinate as a metabolite. In vivo sensing of the tritrichomonad required SUCNR1, whereas N. brasiliensis was SUCNR1 independent. These findings define a paradigm wherein tuft cells monitor microbial metabolites to initiate type 2 immunity and suggest the existence of other sensing pathways triggering the response to helminths.
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•Expression of receptors enabling chemosensing on tuft cells is tissue specific•Tuft cells in the small intestine express the succinate receptor SUCNR1•Succinate is sufficient to induce a multifaceted type 2 immune response•Immune sensing of Tritrichomonas colonization by tuft cells requires SUCNR1
Tuft cells have been proposed to act as immune sentinels in multiple tissues. Nadjsombati and McGinty et al. now show that detection of the microbial metabolite succinate by tuft cells in the small intestine is sufficient to induce a type 2 immune response, suggesting that tuft cells monitor microbial metabolites to initiate type 2 immunity.
The thymus is responsible for generating a diverse yet self-tolerant pool of T cells
. Although the thymic medulla consists mostly of developing and mature AIRE
epithelial cells, recent evidence has ...suggested that there is far greater heterogeneity among medullary thymic epithelial cells than was previously thought
. Here we describe in detail an epithelial subset that is remarkably similar to peripheral tuft cells that are found at mucosal barriers
. Similar to the periphery, thymic tuft cells express the canonical taste transduction pathway and IL-25. However, they are unique in their spatial association with cornified aggregates, ability to present antigens and expression of a broad diversity of taste receptors. Some thymic tuft cells pass through an Aire-expressing stage and depend on a known AIRE-binding partner, HIPK2, for their development. Notably, the taste chemosensory protein TRPM5 is required for their thymic function through which they support the development and polarization of thymic invariant natural killer T cells and act to establish a medullary microenvironment that is enriched in the type 2 cytokine, IL-4. These findings indicate that there is a compartmentalized medullary environment in which differentiation of a minor and highly specialized epithelial subset has a non-redundant role in shaping thymic function.
The thymus' key function in the immune system is to provide the necessary environment for the development of diverse and self-tolerant T lymphocytes. While recent evidence suggests that the thymic ...stroma is comprised of more functionally distinct subpopulations than previously appreciated, the extent of this cellular heterogeneity in the human thymus is not well understood. Here we use single-cell RNA sequencing to comprehensively profile the human thymic stroma across multiple stages of life. Mesenchyme, pericytes and endothelial cells are identified as potential key regulators of thymic epithelial cell differentiation and thymocyte migration. In-depth analyses of epithelial cells reveal the presence of ionocytes as a medullary population, while the expression of tissue-specific antigens is mapped to different subsets of epithelial cells. This work thus provides important insight on how the diversity of thymic cells is established, and how this heterogeneity contributes to the induction of immune tolerance in humans.
Medullary thymic epithelial cells (mTECs) play a critical role in central immune tolerance by mediating negative selection of autoreactive T cells through the collective expression of the peripheral ...self-antigen compartment, including tissue-specific antigens (TSAs). Recent work has shown that gene-expression patterns within the mTEC compartment are heterogenous and include multiple differentiated cell states. To further define mTEC development and medullary epithelial lineage relationships, we combined lineage tracing and recovery from transient in vivo mTEC ablation with single-cell RNA-sequencing in
. The combination of bioinformatic and experimental approaches revealed a non-stem transit-amplifying population of cycling mTECs that preceded
expression. We propose a branching model of mTEC development wherein a heterogeneous pool of transit-amplifying cells gives rise to
- and
-expressing mTEC subsets. We further use experimental techniques to show that within the
expressing developmental branch, TSA expression peaked as
expression decreased, implying
expression must be established before TSA expression can occur. Collectively, these data provide a roadmap of mTEC development and demonstrate the power of combinatorial approaches leveraging both in vivo models and high-dimensional datasets.
•APS-1/APECED patients exhibit marked phenotypic variability despite genotypic similarities.•Defects in AIRE synergize with defects in peripheral tolerance to promote autoimmunity.•Manipulation of ...AIRE-dependent thymic tolerance is an emerging therapeutic target.
AIRE is a well-established master regulator of central tolerance. It plays an essential role in driving expression of tissue-specific antigens in the thymus and shaping the development of positively selected T-cells. Humans and mice with compromised or absent AIRE function have markedly variable phenotypes that include a range of autoimmune manifestations. Recent evidence suggests that this variability stems from cooperation of autoimmune susceptibilities involving both central and peripheral tolerance checkpoints. Here we discuss the broadening understanding of the factors that influence Aire expression, modify AIRE function, and the impact and intersection of AIRE with peripheral immunity. This rapidly expanding body of knowledge will force a reexamination of the definition and clinical management of APS-1 patients as well as provide a foundation for the development of immunomodulatory strategies targeting central tolerance.
The accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates a signaling cascade known as the unfolded protein response (UPR). Although activation of the UPR is well described, ...there is little sense of how the response, which initiates both apoptotic and adaptive pathways, can selectively allow for adaptation. Here we describe the reconstitution of an adaptive ER stress response in a cell culture system. Monitoring the activation and maintenance of representative UPR gene expression pathways that facilitate either adaptation or apoptosis, we demonstrate that mild ER stress activates all UPR sensors. However, survival is favored during mild stress as a consequence of the intrinsic instabilities of mRNAs and proteins that promote apoptosis compared to those that facilitate protein folding and adaptation. As a consequence, the expression of apoptotic proteins is short-lived as cells adapt to stress. We provide evidence that the selective persistence of ER chaperone expression is also applicable to at least one instance of genetic ER stress. This work provides new insight into how a stress response pathway can be structured to allow cells to avert death as they adapt. It underscores the contribution of posttranscriptional and posttranslational mechanisms in influencing this outcome.
The developmental programs that generate a broad repertoire of regulatory T cells (T
cells) able to respond to both self antigens and non-self antigens remain unclear. Here we found that mature T
...cells were generated through two distinct developmental programs involving CD25
T
cell progenitors (CD25
T
P cells) and Foxp3
T
cell progenitors (Foxp3
T
P cells). CD25
T
P cells showed higher rates of apoptosis and interacted with thymic self antigens with higher affinity than did Foxp3
T
P cells, and had a T cell antigen receptor repertoire and transcriptome distinct from that of Foxp3
T
P cells. The development of both CD25
T
P cells and Foxp3
T
P cells was controlled by distinct signaling pathways and enhancers. Transcriptomics and histocytometric data suggested that CD25
T
P cells and Foxp3
T
P cells arose by coopting negative-selection programs and positive-selection programs, respectively. T
cells derived from CD25
T
P cells, but not those derived from Foxp3
T
P cells, prevented experimental autoimmune encephalitis. Our findings indicate that T
cells arise through two distinct developmental programs that are both required for a comprehensive T
cell repertoire capable of establishing immunotolerance.
Aire in Autoimmunity Miller, Corey N; Waterfield, Michael R; Gardner, James M ...
Annual review of immunology,
06/2024, Letnik:
42, Številka:
1
Journal Article
Recenzirano
The role of the autoimmune regulator (Aire) in central immune tolerance and thymic self-representation was first described more than 20 years ago, but fascinating new insights into its biology ...continue to emerge, particularly in the era of advanced single-cell genomics. We briefly describe the role of human genetics in the discovery of Aire, as well as insights into its function gained from genotype-phenotype correlations and the spectrum of Aire-associated autoimmunity-including insights from patients with Aire mutations with broad and diverse implications for human health. We then highlight emerging trends in Aire biology, focusing on three topic areas. First, we discuss medullary thymic epithelial diversity and the role of Aire in thymic epithelial development. Second, we highlight recent developments regarding the molecular mechanisms of Aire and its binding partners. Finally, we describe the rapidly evolving biology of the identity and function of extrathymic Aire-expressing cells (eTACs), and a novel eTAC subset called Janus cells, as well as their potential roles in immune homeostasis. Expected final online publication date for the
, Volume 42 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Thymic central tolerance is essential to preventing autoimmunity. In medullary thymic epithelial cells (mTECs), the Autoimmune regulator (Aire) gene plays an essential role in this process by driving ...the expression of a diverse set of tissue-specific antigens (TSAs), which are presented and help tolerize self-reactive thymocytes. Interestingly, Aire has a highly tissue-restricted pattern of expression, with only mTECs and peripheral extrathymic Aire-expressing cells (eTACs) known to express detectable levels in adults. Despite this high level of tissue specificity, the cis-regulatory elements that control Aire expression have remained obscure. Here, we identify a highly conserved noncoding DNA element that is essential for Aire expression. This element shows enrichment of enhancer-associated histone marks in mTECs and also has characteristics of being an NF-κB-responsive element. Finally, we find that this element is essential for Aire expression in vivo and necessary to prevent spontaneous autoimmunity, reflecting the importance of this regulatory DNA element in promoting immune tolerance.
The basic two-step terminal differentiation model of the medullary thymic epithelial cell (mTEC) lineage from immature MHC class II (MHCII)
to mature MHCII
mTECs has recently been extended to include ...a third stage, namely the post-Aire MHCII
subset as identified by lineage-tracing models. However, a suitable surface marker distinguishing the phenotypically overlapping pre- from the post-Aire MHCII
stage has been lacking. In this study, we introduce the lectin
agglutinin (TPA) as a novel cell surface marker that allows for such delineation. Based on our data, we derived the following sequence of mTEC differentiation: TPA
MHCII
→ TPA
MHCII
→ TPA
MHCII
→ TPA
MHCII
Surprisingly, in the steady-state postnatal thymus TPA
MHCII
pre-Aire rather than terminally differentiated post-Aire TPA
MHCII
mTECs were marked for apoptosis at an exceptionally high rate of ∼70%. Hence, only the minor cycling fraction of the MHCII
subset (<20%) potentially qualified as mTEC precursors. FoxN1 expression inversely correlated with the fraction of slow cycling and apoptotic cells within the four TPA subsets. TPA also further subdivided human mTECs, although with different subset distribution. Our revised road map emphazises close parallels of terminal mTEC development with that of skin, undergoing an alternative route of cell death, namely cornification rather than apoptosis. The high rate of apoptosis in pre-Aire MHCII
mTECs points to a "quality control" step during early mTEC differentiation.
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