Immunological Reviews最新文献

Anaphylaxis is a life-threatening immunoglobulin E (IgE)-mediated type I hypersensitivity reaction with rising prevalence and burden. It involves mast cell degranulation upon cross-linking of antigen on mast cell-bound IgE. Mechanisms of IgE-mediated anaphylaxis remain incompletely understood, particularly the induction of systemic symptoms (hypothermia, hypotension). We consider two hypotheses driving anaphylaxis. In the first case, circulating antigen reaches mast cells systemically, causing widespread degranulation and downstream effects. In a second scenario, a subset of mast cells “view” antigen, initiating local activation and extensive neuronal signaling to activate distal mast cells and trigger tissue responses. Support for systemic antigen is evident in food allergy, with allergenicity determined by antigen stability in the face of digestion, and antigen translocation across the gut epithelium and within circulation, possibly through chylomicrons. Emerging research implicates neuronal signaling in modulating systemic responses, with mast cells communicating bidirectionally with neurons via released mediators. These interactions lower activation thresholds, amplify inflammation, and engage key downstream receptors and pathways. In vivo models demonstrate such mast cell neuromodulation underlying systemic manifestations of IgE-mediated anaphylaxis, including pruritus and hypothermia. The evidence suggests that both scenarios are likely at play in anaphylaxis, warranting further investigation.

The immune system is tasked with mounting effective responses to pathogens while preventing inflammation triggered by innocuous antigens, including those derived from self, food, and commensal microbes. This balance is especially critical in the intestine, where dietary and microbial antigens are constantly encountered. Peripherally induced regulatory T cells (pTreg or iTreg) play a key role in suppressing inappropriate immune activation and maintaining gut homeostasis. Elucidating how pTreg cells are generated along the gastrointestinal tract is therefore critical to understanding peripheral tolerance. Recent studies have revealed that intestinal antigen-specific pTreg cell differentiation is induced by a distinct lineage of antigen-presenting cells (APCs) requiring expression of the transcription factors RORγt and PRDM16. Genetic perturbation of these APCs results not only in microbiota-specific proinflammatory T cell responses but also in the breakdown of oral tolerance, which in turn predisposes to allergic inflammation. In this review, we summarize the discovery of these tolerance-inducing APCs, highlight their role in instructing pTreg cell differentiation in response to microbiota and dietary antigens, and discuss the regulatory networks that support their function during intestinal immune tolerance.

Immune surveillance of tissues is primarily carried out by dendritic cells (DCs), which act as sentinels for the adaptive immune system. To accomplish this task, DCs migrate from tissues to regional lymph nodes, or from blood-exposed regions of the spleen to the white pulp, to prime T cell responses. DC migration is a tightly regulated process that occurs at both steady state and during inflammation, and is dependent on sensing a wide array of chemoattractant molecules. Migration involves dynamic cytoskeletal rearrangement after signaling from chemotactic receptors, followed by rapid chemotaxis to specific regions of lymphoid tissues along gradients of chemoattractant molecules. In this review, we explore how DCs regulate the process of migration at the level of activation and receptor expression, chemoattractant sensing, and signaling to induce cytoskeletal rearrangement. We discuss differences in how DC subsets migrate, including the different regions these subsets localize to within lymphoid tissues and how these differences impact T cell responses. We also examine DC migration in the context of diverse tissue environments, with a focus on barrier sites. This comparison contributes to a holistic understanding of the common ways DC migration is regulated, as well as key differences that contribute to divergent adaptive immune responses.

Transitional dendritic cells (tDCs) have emerged as a compelling addition to the dendritic cell (DC) network—a hybrid subset that bridges plasmacytoid (pDC) and conventional (cDC) lineages, particularly conventional type 2 DCs (cDC2s). First identified through high-dimensional single-cell profiling, tDCs combine features of both pDCs and cDC2s yet follow a distinct developmental trajectory with unique effector functions. Although ontogenetically related to pDCs, tDCs do not produce type I interferon but instead mount a robust IL-1β response upon pathogen sensing, positioning them as rapid initiators of innate inflammation. tDCs also mirror cDC2s in their ability to capture antigen and prime naïve CD4⁺ T cells. Importantly, tDCs exist in progressive states—tDC^lo, tDC^hi, CD11b⁻ tDC2s and tDC-derived DC2s (tDC2s)—reflecting a unidirectional differentiation continuum. Recognizing this dynamic spectrum is essential for properly interpreting tDC function and avoiding fragmented nomenclature. In this review, we synthesize current insights into tDC biology across species—tracing their origin, phenotypic and transcriptional trajectory, tissue localization, and immune function. Although tDCs challenge the rigid pDC/cDC dichotomy, they exemplify a broader principle: DC identity is not fixed but temporally programmed, even during homeostasis. Embracing this plasticity may unlock new opportunities for therapeutic intervention in infection, cancer, and autoimmunity.

Type 2 conventional dendritic cells (cDC2s) are central orchestrators of adaptive immunity. While historically considered a single population shaped by local microenvironments, recent evidence indicates that cDC2s comprise developmentally distinct subsets—cDC2As and cDC2Bs—with divergent ontogeny, tissue distribution, and immune functions. This review synthesizes current advances in the identification, differentiation, and functional characterization of these cDC2 subsets, with a focus on data supporting an early bifurcation at the level of bone marrow progenitors. We highlight how transcription factors such as TCF4 (and RBPJ) and KLF4 delineate cDC2A and cDC2B fates, respectively, and how subset-specific localization within tissues may amplify their distinct roles in immunity. We propose that early cDC2 diversification reflects a broader principle of central immune preconfiguration, in which the bone marrow senses peripheral immunological states and anticipates tissue-specific demands through progenitor programming. This hypothetical model redefines cDC2s not merely as adaptable responders to local cues, but as a paradigm for how immune output can be systemically preconfigured. As such, they offer a powerful lens through which to study how development and function intersect across immunity. Recent findings suggest that the ontogenetic logic in mouse cDC2 development may extend to humans, offering meaningful avenues for translational exploration.

Central tolerance in the thymus ensures that the developing T cell repertoire is safe yet effective against infections. This process relies greatly on antigen presentation by both stromal and hematopoietic antigen-presenting cells (APCs), with dendritic cells (DCs) playing a particularly critical role. Thymic DCs acquire a broad spectrum of self-antigens, including tissue-restricted antigens (TRAs), inflammation-associated antigens (ISAs), and peripheral antigens imported via circulation or immigrating DCs. These diverse inputs allow DCs to mediate clonal deletion, regulatory T cell (Treg) induction, and other agonist selection outcomes. In this review, we revisit thymic DCs, outlining their ontogeny, transcriptional control, and functional specialization. We compare thymic DC1 and DC2 subsets with their peripheral counterparts, highlighting their distinct localizations, maturation cues, and division of labor: DC1 excel in cross-presentation and Treg generation, while DC2 preferentially drive clonal deletion. We also highlight the heterogeneity of DC2s, which consist of four distinct subsets based on their transcriptional and phenotypic programs. We further examine plasmacytoid DCs, transitional DCs, monocytes, and macrophages, which contribute to tolerance through apoptotic cell clearance, antigen transfer, and lineage diversion of thymocytes. Finally, we discuss the role of homeostatic maturation, sterile inflammatory cues, and thymic immigration in shaping APC diversity. Together, these insights underscore the heterogeneity of thymic APCs, the complexity of thymic DC biology, and its vital importance in enforcing immune self-tolerance.