Immunological Reviews最新文献

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.

Dendritic cells comprise several populations with distinct ontogeny that share core features including a typical dendritic morphology and the ability to present antigens and stimulate T cells. Dendritic cells originating from monocytes have been reported in steady-state and in different inflammatory contexts, in mouse models and in human clinical samples. However, because of their phenotypical and transcriptional proximity with other dendritic cell subsets and with monocyte-derived macrophages, whether monocyte-derived dendritic cells (mo-DCs) represent a distinct population has been controversial. Here, we summarize the evidence supporting the existence of mo-DCs in vivo and we review work addressing the molecular regulation of mo-DCs differentiation and their role in immune responses. We also discuss the potential for harnessing mo-DCs differentiation for therapy.

Decades of experimental work have helped define the heterogeneity of the various cell types that compose the immune system. The different cell types arise from distinct hematopoietic stem and progenitor cells in a coordinated fashion during ontogeny, providing a set of diverse cells that contribute to host defense. Cells can also differentiate into different subsets in response to the cytokine and tissue environment, creating a level of cellular heterogeneity that helps direct the nature and magnitude of the immune response. Here we are discussing a variation whereby cellular heterogeneity arises due to the expression of X-linked immune genes that escape X chromosome inactivation, giving an advantage to a subset of cells more prone to respond to stimulation by external (pathogens) but also internal signals (i.e., mechanosensing). Interestingly, these inflammatory subsets are much more likely to be differentially enriched in patients with autoimmunity or inflammatory diseases which are well known to be predominant in females. We are using plasmacytoid dendritic cells (pDCs) as a model cell type, as these cells are a rare but critical subset of innate immune cells, with a rapid and massive capacity to produce type I IFNs (IFN-I) upon sensing of nucleic acids from pathogens, but also from the self, and these cells have been linked to the pathogenesis of many autoimmune diseases.

Dendritic cells (DCs) play a crucial role in bridging innate and adaptive immunity by presenting antigens to prime antigen-specific T cells. Conventional DC (cDC) type 2 cells (cDC2s) are a phenotypically heterogeneous population of DCs highly capable of presenting antigens to CD4+ T cells. Studies found functional differences between different cDC2 subsets in regulating effector CD4+ T helper (Th) cells, but collaboration between different cDC subsets has also been suggested. In this review, we discuss recent advances in understanding the subset-specific role of cDC2s in regulating Th cells.

Initial description of extrafollicular B cell responses (EF) identified them as short-lived clusters of rapidly proliferating B cells and plasmablasts in splenic bridging channels and red pulp as well as lymph node medullary cord areas. Their physical location guided the nomenclature: outside, or at the edges of B cell follicles and near T cell zones of secondary lymphoid organs, thus distinct from the follicular situated germinal centers (GCs). Because EFs are often induced transiently and to both T-dependent and T-independent antigens, and because they generate IgM and class-switched antibodies often with no or little signs of somatic hypermutations, they were thought to be less impactful than GC-derived antibodies. However, highly protective antibodies are generated by these EFs rapidly after acute infections and their induction often correlates with pathogen clearance, while in autoimmunity EF-derived antibodies have been implicated as pathogenic drivers of disease. Moreover, subsets of memory B cells, including some CD11c+ “atypical” B cells/ABCs are generated independently of GC. Their diverse appearance and impact have initiated an ongoing debate about whether all “non-GC responses” are necessarily EF responses. The current debate is reflected also in the articles compiled for this issue of Immunological Reviews considering EF responses. Here, I briefly summarize the steps leading to B cell activation and EF and GC formation, providing context for the contributed reviews that span a breadth of topics from descriptions of non-GC responses in jawed non-mammalian vertebrates as possible orthologues of mammalian EF to the molecular and metabolic requirements and CD4 T cell helper quality of EF, tissue-specific B cell responses, and discussions on the origins and classifications of “atypical” memory B cells in mice and man.