Dendritic cells, macrophages and B cells are regarded as the classical antigen-presenting cells of the immune system. However, in recent years, there has been a rapid increase in the number of cell ...types that are suggested to present antigens on MHC class II molecules to CD4(+) T cells. In this Review, we describe the key characteristics that define an antigen-presenting cell by examining the functions of dendritic cells. We then examine the functions of the haematopoietic cells and non-haematopoietic cells that can express MHC class II molecules and that have been suggested to represent 'atypical' antigen-presenting cells. We consider whether any of these cell populations can prime naive CD4(+) T cells and, if not, question the effects that they do have on the development of immune responses.
How commensal microbiota contributes to immune cell homeostasis at barrier surfaces is poorly understood. Lamina propria (LP) T helper 17 (Th17) cells participate in mucosal protection and are ...induced by commensal segmented filamentous bacteria (SFB). Here we show that MHCII-dependent antigen presentation of SFB antigens by intestinal dendritic cells (DCs) is crucial for Th17 cell induction. Expression of MHCII on CD11c+ cells was necessary and sufficient for SFB-induced Th17 cell differentiation. Most SFB-induced Th17 cells recognized SFB in an MHCII-dependent manner. SFB primed and induced Th17 cells locally in the LP and Th17 cell induction occurred normally in mice lacking secondary lymphoid organs. The importance of other innate cells was unveiled by the finding that MHCII deficiency in group 3 innate lymphoid cells (ILCs) resulted in an increase in SFB-independent Th17 cell differentiation. Our results outline the complex role of DCs and ILCs in the regulation of intestinal Th17 cell homeostasis.
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•Presentation of SFB antigens by iDC is required for Th17 cell induction by SFB•SFB-induced Th17 cells recognize SFB antigens•SFB prime CD4 T cells and induce Th17 cell differentiation in the gut mucosa•Loss of MHCII on RORγt ILC leads to Th17 cell differentiation in the absence of SFB
T follicular helper (Tfh) cells are a critical component of adaptive immunity and assist in optimal Ab‐mediated defense. Multiple effector functions of Tfh support germinal center B cell survival, Ab ...class switching, and plasma cell maturation. In the past 2 decades, the phenotype and functional characteristics of GC Tfh have been clarified allowing for robust studies of the Th subset including activation signals and environmental cues controlling Tfh differentiation and migration during an immune response. A unique, 2‐step differentiation process of Tfh has been proposed but the mechanisms underlying transition between unstable Tfh precursors and functional mature Tfh remain elusive. Likewise, newly identified transcriptional regulators of Tfh development have not yet been incorporated into our understanding of how these cells might function in disease. Here, we review the signals and downstream transcription factors that shape Tfh differentiation including what is known about the epigenetic processes that maintain Tfh identity. It is proposed that further evaluation of the stepwise differentiation pattern of Tfh will yield greater insights into how these cells become dysregulated in autoimmunity.
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Transcriptional regulation and epigenetic remodeling stabilize Tfh subset identity and require multiple APC‐mediated stages of activation
T helper type 2 (T(H)2)-mediated immune responses are induced after infection with multicellular parasites and can be triggered by a variety of allergens. The mechanisms of induction and the ...antigen-presenting cells involved in the activation of T(H)2 responses remain poorly defined, and the innate immune sensing pathways activated by parasites and allergens are largely unknown. Basophils are required for the in vivo induction of T(H)2 responses by protease allergens. Here we show that basophils also function as antigen-presenting cells. We show that although dendritic cells were dispensable for allergen-induced activation of T(H)2 responses in vitro and in vivo, antigen presentation by basophils was necessary and sufficient for this. Thus, basophils function as antigen-presenting cells for T(H)2 differentiation in response to protease allergens.
Inflammatory CD4⁺ T cell responses to self or commensal bacteria underlie the pathogenesis of autoimmunity and inflammatory bowel disease (IBD), respectively. Although selection of self-specific T ...cells in the thymus limits responses to mammalian tissue antigens, the mechanisms that control selection of commensal bacteria-specific T cells remain poorly understood. Here, we demonstrate that group 3 innate lymphoid cell (ILC3)-intrinsic expression of major histocompatibility complex class II (MHCII) is regulated similarly to thymic epithelial cells and that MHCII⁺ ILC3s directly induce cell death of activated commensal bacteria-specific T cells. Further, MHCII on colonie ILC3s was reduced in pediatric IBD patients. Collectively, these results define a selection pathway for commensal bacteria-specific CD4⁺ T cells in the intestine and suggest that this process is dysregulated in human IBD.
Microbial colonization of the mammalian intestine elicits inflammatory or tolerogenic T cell responses, but the mechanisms controlling these distinct outcomes remain poorly understood, and ...accumulating evidence indicates that aberrant immunity to intestinal microbiota is causally associated with infectious, inflammatory and malignant diseases
. Here we define a critical pathway controlling the fate of inflammatory versus tolerogenic T cells that respond to the microbiota and express the transcription factor RORγt. We profiled all RORγt
immune cells at single-cell resolution from the intestine-draining lymph nodes of mice and reveal a dominant presence of T regulatory (T
) cells and lymphoid tissue inducer-like group 3 innate lymphoid cells (ILC3s), which co-localize at interfollicular regions. These ILC3s are distinct from extrathymic AIRE-expressing cells, abundantly express major histocompatibility complex class II, and are necessary and sufficient to promote microbiota-specific RORγt
T
cells and prevent their expansion as inflammatory T helper 17 cells. This occurs through ILC3-mediated antigen presentation, αV integrin and competition for interleukin-2. Finally, single-cell analyses suggest that interactions between ILC3s and RORγt
T
cells are impaired in inflammatory bowel disease. Our results define a paradigm whereby ILC3s select for antigen-specific RORγt
T
cells, and against T helper 17 cells, to establish immune tolerance to the microbiota and intestinal health.
Effective major histocompatibility complex-II (MHC-II) antigen presentation from phagocytosed particles requires phagosome-intrinsic Toll-like receptor (TLR) signaling, but the molecular mechanisms ...underlying TLR delivery to phagosomes and how signaling regulates antigen presentation are incompletely understood. We show a requirement in dendritic cells (DCs) for adaptor protein-3 (AP-3) in efficient TLR recruitment to phagosomes and MHC-II presentation of antigens internalized by phagocytosis but not receptor-mediated endocytosis. DCs from AP-3-deficient pearl mice elicited impaired CD4+ T cell activation and Th1 effector cell function to particulate antigen in vitro and to recombinant Listeria monocytogenes infection in vivo. Whereas phagolysosome maturation and peptide:MHC-II complex assembly proceeded normally in pearl DCs, peptide:MHC-II export to the cell surface was impeded. This correlated with reduced TLR4 recruitment and proinflammatory signaling from phagosomes by particulate TLR ligands. We propose that AP-3-dependent TLR delivery from endosomes to phagosomes and subsequent signaling mobilize peptide:MHC-II export from intracellular stores.
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► AP-3 is selectively required for optimal MHC-II presentation of phagocytosed antigen ► AP-3-deficient dendritic cells induce impaired CD4+ T cell inflammatory responses ► AP-3 regulates TLR4 delivery to phagosomes and subsequent inflammatory signaling ► AP-3 regulates phagosomal peptide:MHC-II complex delivery to the cell surface
T follicular helper cells (Tfh), a subset of CD4+ T cells, provide requisite help to B cells in the germinal centers (GC) of lymphoid tissue. GC Tfh are identified by high expression of the chemokine ...receptor CXCR5 and the inhibitory molecule PD-1. Although more accessible, blood contains lower frequencies of CXCR5+ and PD-1+ cells that have been termed circulating Tfh (cTfh). However, it remains unclear whether GC Tfh exit lymphoid tissues and populate this cTfh pool. To examine exiting cells, we assessed the phenotype of Tfh present within the major conduit of efferent lymph from lymphoid tissues into blood, the human thoracic duct. Unlike what was found in blood, we consistently identified a CXCR5-bright PD-1-bright (CXCR5BrPD-1Br) Tfh population in thoracic duct lymph (TDL). These CXCR5BrPD-1Br TDL Tfh shared phenotypic and transcriptional similarities with GC Tfh. Moreover, components of the epigenetic profile of GC Tfh could be detected in CXCR5BrPD-1Br TDL Tfh and the transcriptional imprint of this epigenetic signature was enriched in an activated cTfh subset known to contain vaccine-responding cells. Together with data showing shared TCR sequences between the CXCR5BrPD-1Br TDL Tfh and cTfh, these studies identify a population in TDL as a circulatory intermediate connecting the biology of Tfh in blood to Tfh in lymphoid tissue.
Despite the importance of programmed cell death-1 (PD-1) in inhibiting T cell effector activity, the mechanisms regulating its expression remain poorly defined. We found that the chromatin organizer ...special AT-rich sequence-binding protein-1 (Satb1) restrains PD-1 expression induced upon T cell activation by recruiting a nucleosome remodeling deacetylase (NuRD) complex to Pdcd1 regulatory regions. Satb1 deficienct T cells exhibited a 40-fold increase in PD-1 expression. Tumor-derived transforming growth factor β (Tgf-β) decreased Satb1 expression through binding of Smad proteins to the Satb1 promoter. Smad proteins also competed with the Satb1-NuRD complex for binding to Pdcd1 enhancers, releasing Pdcd1 expression from Satb1-mediated repression, Satb1-deficient tumor-reactive T cells lost effector activity more rapidly than wild-type lymphocytes at tumor beds expressing PD-1 ligand (CD274), and these differences were abrogated by sustained CD274 blockade. Our findings suggest that Satb1 functions to prevent premature T cell exhaustion by regulating Pdcd1 expression upon T cell activation. Dysregulation of this pathway in tumor-infiltrating T cells results in diminished anti-tumor immunity.
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•T cell activation increased the expression of Satb1 in mature CD8+ and CD4+ T cells•Recruitment of the NuRD repression complex by Satb1 inhibits expression of Pdcd1•In tumors, TGF-β inhibits Satb1 expression in T cells, increasing Pdcd1 expression•Satb1−/− T cells express high amounts of PD-1 and have decreased anti-tumor activity
Stephen et al. show that the chromatin organizer Satb1 controls expression levels of PD-1 upon T cell activation through the recruitment of a de-acetylase complex to regulatory regions of the Pdcd1 gene. Tumor-derived TGF-β dysregulates this pathway, unleashing PD-1 expression in tumor-infiltrating T cells and decreasing anti-tumor immunity.
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