Immunological Reviews最新文献

Lymphoid aggregates and more mature tertiary lymphoid structures frequently form within chronically inflamed tissues. These structures facilitate local T cell-B cell activation within an inflamed tissue, promoting the ongoing adaptive immune response. Target tissues in autoimmune diseases accumulate a range of CD4 T cells with the capacity to help B cells and promote lymphoid aggregate formation. These B cell-helper T cells include T peripheral helper (Tph) cells, which functionally resemble T follicular helper (Tfh) cells in their capacity to recruit and interact with B cells, yet differ primarily in their migratory capacity. Tph cells accumulate within inflamed tissues such as rheumatoid arthritis synovium, where they serve as a major source of the B cell chemoattractant CXCL13, which can drive recruitment of B cells to a peripheral tissue. Here, we discuss features of Tph cells and other Tfh-like T cell populations that accumulate within chronically inflamed tissues in autoimmune diseases and review the regulation of key factors produced by these cells, including CXCL13 and IL-21. Understanding the range of B cell-helper T cells that accumulate within tissues and the regulation of their differentiation and function may provide new strategies to either inhibit or promote their actions therapeutically.

Plasmacytoid dendritic cells (pDCs) are best known for their outstanding ability to rapidly produce large amounts of type I interferons (IFN-I), which are key antiviral mediators. However, after their initial IFN-I burst, the pDC lineage undergoes a number of adaptations that converge on the attenuation of pDC-derived interferons, ensuring their production remains short-lived regardless of whether the pathogen is cleared or persists. The convergence of multiple host adaptations that result in reduced pDC numbers and/or function after infection highlights the double-edged sword nature of pDCs: while they can be beneficial for antiviral defense, they can also drive tissue pathology. In this review, we summarize selected pDC-lineage adaptations that arise after their initial IFN-I peak following a viral infection, including compromised pDC development from bone marrow progenitors, fate plasticity that enables pDC conversion into conventional dendritic cells type 2 (cDC2)–like cells, and loss of the pDCs' hallmark capacity to produce IFN-I. We also provide an overview of the underlying molecular mechanisms contributing to the aforementioned adaptations, discuss potential evolutionary advantages, and highlight future avenues to dissect the fundamental biology of pDC reprogramming with the ultimate goal of leveraging these insights to therapeutically target pDCs in infections and beyond.

Lymph nodes (LNs) are highly organized secondary lymphoid organs that serve as critical hubs for immune defense. They filter lymph and enable efficient immune surveillance, elicit potent innate responses to prevent systemic pathogen spread, and generate adaptive immunity for long-lived protection. It has now been established that conventional dendritic cells (DCs), canonically recognized as professional antigen-presenting cells that instruct T cell responses, play foundational roles in coordinating all these functions of the LN. DCs are the most abundant innate cell type in the LN parenchyma, and their ability to mediate these processes is intimately tied to their spatial organization. Rather than being randomly dispersed, different DC subsets preferentially occupy distinct niches within the tissue. This positioning regulates their homeostatic maintenance, access to different types of antigens, and interactions with other immune cells, which collectively shape the ensuing immune response. In this review, we summarize the current understanding of how the spatiotemporal dynamics and functional cooperation of DC subsets, and other innate populations, underpin diverse immunological functions of the LN, ranging from steady-state surveillance to the development of synchronized and tailored innate and adaptive responses to pathogens or following vaccination.

The development of type 1 classical dendritic cells (cDC1s) from bone marrow progenitors is a multistage process directed by a complex transcriptional network. At its center is interferon regulatory factor-8 (IRF8), the lineage-determining factor whose precise, stage-specific expression is integrated at the Irf8 super-enhancer. This developmental sequence is initiated in early progenitors by C/EBPα acting at the +56 kb Irf8 enhancer. As progenitors transition to the common dendritic cell progenitor (CDP), the E-protein activity at the +41 kb Irf8 enhancer further augments the level of IRF8 expression. This progression is followed by a critical “enhancer switch” network, in which NFIL3 induced in the CDP suppresses ZEB2, causing de-repression of both ID2 and BATF3. This step terminates the +41 kb enhancer's activity while simultaneously engaging the +32 kb enhancer, where newly induced BATF3 forms a stable auto-regulatory loop with IRF8 and JUN to lock in the cDC1 fate. A notable feature of the +32 kb Irf8 enhancer is its low-affinity elements that purposely detune factor binding, called suboptimization, a property that is critical for the divergence of the cDC1 and cDC2 progenitors. The development of the cDC1 can also be abrogated in settings that disturb the normal balance of Zeb2 repression by NFIL3 and activation by C/EBP factors. Tumors producing IL-6 systemically can elevate C/EBPβ in CDPs to a point where NFIL3 fails to induce cDC1 specification. Finally, studies of compound enhancer deletions reveal that this cascade is governed by a strictly cis-dependent mechanism: the function of each subsequent enhancer is contingent on the successful prior activation of the preceding enhancer on the same chromosome. This sequential, cis-regulated activation appears to be the core mechanism for progressively tuning chromatin accessibility, ensuring robust lineage commitment. While its molecular basis is obscure, this dependency offers a new model for understanding genomic regulation in development.

Dendritic cells (DCs) are essential regulators of adaptive immunity, functioning as professional antigen-presenting cells that bridge innate sensing with the induction of adaptive immunity and immune memory. The DC population is heterogeneous, encompassing numerous phenotypic subsets depending on the tissue, pathophysiological condition and species studied, which historically complicated their classification. Advances in bulk or single-cell transcriptomics and ontogenetic studies have clarified DC heterogeneity and highlighted type 1 conventional DCs (cDC1s) for their unique ability to induce protective CD8⁺ T cell responses against cancer and intracellular pathogens. Beyond immunity, DCs also maintain tolerance to self and harmless antigens. Contrary to earlier assumptions that tolerogenic DCs are simply immature, recent evidence shows that both immunogenic and tolerogenic maturation involve an extensive and convergent reprogramming of cDC1s during the activation process licensing them for shaping T cell responses, a process referred to as DC maturation. This evolving understanding is reshaping how we study DCs, including the necessity to integrate the timing of DC maturation and their microanatomical redistribution during this process. The novel insights these studies are bringing carry significant implications for vaccines or immunotherapies against intracellular pathogens or cancers, and treatments against allergy or autoimmunity.