Immunological Reviews最新文献

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a major public health burden responsible for over a million deaths each year. A deeper understanding of the mechanisms that balance protective immunity and immunopathology is essential for developing more effective therapeutics. This review focuses on the dynamic interplay between CD4⁺ T cells and B cells in the lung, with an emphasis on their interactions in tertiary lymphoid structures (TLS). TLS are immune cell aggregates that arise in inflamed, nonlymphoid tissues, range from loosely to highly organized clusters, and serve as localized hubs for immune cell interaction, activation, and diversification. Drawing on insights from other disease contexts, including infections, cancer, and chronic inflammatory conditions, we examine the molecular signals and cellular interactions involved in TLS formation, maintenance, and function during Mtb infection. Additionally, we explore the anatomical and functional integration of TLS with the lymphatic and vascular systems, and how this spatial organization may influence bacterial persistence and dissemination. Clarifying the functional role of TLS in TB—whether they support protective immunity, contribute to lung pathology, or both—could inform novel approaches to modulate local immune responses and improve TB disease outcomes.

The cover image is based on the article by Cornelia Weyand Structures in Autoimmune Disease by Cornelia Weyand et al., https://doi.org/10.1111/imr.70047

In this review, we examine different mechanisms for the generation of pathological IgE through the study of inborn errors of immunity (IEI). In particular, we focus on IEIs that are susceptible to atopic disease, such as severe eczema, eosinophilia, and/or food anaphylaxis; this group of approximately 50 genes has been coined primary atopic disorders (PADs). PADs link specific genes and pathways to atopic disease and the production of IgE and can provide insights into more common allergies experienced by the general population.

First considered as a negative epiphenomenon in autoimmune and inflammatory diseases, with possible deleterious consequences through the production of pathological autoantibodies and antiself T cells, tertiary lymphoid structures (TLS) have gained major scientific and clinical interest in cancer due to their association with better clinical outcomes and improved responses to immunotherapy. Studies have investigated the structure and plasticity of TLS in the context of tumors and the role of the TLS B-cell compartment in contributing to the favorable clinical outcome of cancer patients. Identifying biomarkers that indicate the presence of TLS in tumors in a noninvasive manner could therefore represent a major advance in the diagnosis and treatment decision-making for these patients. Also, the interplay between TLS, tumor cells, and microbiota opens new avenues for deciphering the role of microorganisms in cancer development. Their use as TLS inducers further underlines the need for continued research in this field. Moreover, emerging data have emphasized the critical role of sensory and sympathetic nerves in regulating TLS formation and function. Finally, humanized mice may serve as valuable tools for developing preclinical models to study the role of human TLS in cancer, a much-needed goal. These different topics are discussed in the present review.

Leptomeningeal tertiary lymphoid structures (TLS) have emerged as a relatively common pathological feature of autoimmune disease, including multiple sclerosis (MS) and particularly in people with progressive and nonremitting MS. These ectopic lymphoid aggregates, observed in the leptomeninges adjacent to so-called “Type 3” sub-pial cortical lesions, are associated with more severe gray matter damage and worse clinical outcomes. Mouse models of MS that recapitulate TLS formation in the central nervous system (CNS) have provided critical insights into the mechanisms driving their development and maintenance. In these models of experimental autoimmune encephalomyelitis (EAE) initiation of TLS is facilitated by Th17 cells, which promote chronic inflammation via cytokines such as IL-17 and GM-CSF. The cell surface expression of lymphotoxin-α and lymphotoxin-β heterotrimers (LTαβ) on lymphocytes, including Th17 cells, elaborates the organization of ectopic lymphoid tissues via LTβR signaling on radio-resistant stromal cells and resident fibroblasts. Ultimately a pro-inflammatory environment characterized by cytokines such as IL-17 and GM-CSF promotes the recruitment of neutrophils which produce proteases and chemokines that sustain a pro-inflammatory milieu. Emerging EAE data suggest that disrupting TLS organization or targeting key pathways involved in their maintenance could represent promising strategies for modulating chronic CNS inflammation in MS. Understanding the cellular and molecular mechanisms regulating TLS dynamics is therefore critical for the development of therapies aimed at halting or reversing nonremitting MS disease.

The thymus is essential for adaptive immunity, orchestrating the differentiation of hematopoietic progenitors into various T-cell lineages. Thymic epithelial cells (TECs) impart this unique function by mediating the major checkpoints in T-cell differentiation while also imposing stringent tolerance processes required to prevent autoimmunity. Achieving these feats requires extensive TEC specialization and the formation of distinct thymic microenvironments. These features change extensively throughout life, from the growth phases of the embryonic and perinatal thymus, into the steady-state adult, through responses to acute injury and regeneration and, finally, during age-related thymic involution. Here we review how hypothesis and technology have shaped the field's understanding of the thymic microenvironment. We focus on how the development of single-cell technologies has revealed a remarkably diverse cellular landscape shaped by progenitor cell differentiation, TEC proliferation, AIRE-mediated transcriptional processes, and the differentiation of thymic mimetic cell lineages.