Immunological Reviews最新文献

Lymphoid organ development occurs in ontogeny in the absence of antigenic stimulation; inflammation occurs after some immunological insult. These subjects had originally been considered as separate fields of research. Inflammation is due to inflammatory mediators such as lymphotoxin (LT) and its close relative, tumor necrosis factor (TNF). The two fields converged with the realization that LT is also crucial for secondary lymphoid organ (SLO) development and that it induces chronic lymphoid infiltrates, called tertiary lymphoid organs (TLOs) or tertiary lymphoid structures (TLSs) that are remarkably like SLOs. TLSs, which were initially described in mice transgenic for the rat insulin promoter driving LT (RIPLT mice), occur in chronic inflammation in autoimmune diseases, atherosclerosis, graft rejection, microbial infection, aging, and cancer. The thesis presented here is that understanding SLO development, structure, and function is key to understanding TLSs. Key discoveries are presented which include the observations that LT's two forms, LTα3 and LTα1β2, signal through different receptors that induce both SLOs and TLSs. Similarities and differences between TLSs and SLOs are presented. Prospects for their inhibition in autoimmune diseases where they are detrimental, and induction in cancer, where they are beneficial, are presented. Challenges and future directions are discussed.

Tertiary lymphoid structures (TLSs) arise in non-lymphoid tissues in response to persistent antigen stimulation and chronic inflammation. Spanning organs from lung and liver to meninges, skin, and beyond, TLSs range from loose aggregates of immune cells to fully mature structures containing functional germinal centers (GC). In this review, we provide a comprehensive overview of TLS formation, architecture, and function across diverse tissues, highlighting both shared features and tissue-specific adaptations. We then explore the clinical relevance of TLS in infections, autoimmunity, cancer, and allergy, emphasizing their dual roles in mediating protective immunity and driving pathology. Finally, we discuss emerging technologies that are transforming our ability to dissect TLSs at high resolution (including spatial multi-omics, advanced imaging, and digital pathology), enabling mechanism-guided strategies to modulate TLSs therapeutically. Framing TLSs through the lens of maturation and tissue context provides a foundation for interpreting their clinical associations and for enhancing or dismantling these niches according to need.

The skin is the outermost organ that serves as the host's live, microbiota-inhabited physical border, evolved to cope with continuous confrontation by a wide variety of environmental elements. This dynamic borderline is prone to injury and damage. Therefore, to deliver on the critical demands for protection, skin is tightly associated with innate and adaptive defense mechanisms that ensure homeostatic tissue barrier integrity. We recently described the skin's ability to form its own autonomous and protective immune response independently of known professional organs. Cutaneous immunocompetence was achieved through the formation of dermal tertiary lymphoid organs (TLOs) that provide protective humoral activity similar to the classical germinal center reaction in the lymph node. This response was mediated by cutaneous microbiota uncoupled from inflammatory signals and positioned within the healthy skin. Our findings illustrate the power of non-inflammatory host-microbiota interaction and open a door for reevaluation of topical disease development and progression. A detailed understanding of highly coordinated tissue-specific determinants that facilitate local antibody response may provide innovative solutions in skin health care and therapies. In this review, I elaborate on our findings and argue for TLO's importance in the host's immune arsenal, which is at the very center of skin's humoral immunity.

Humoral immune responses are critical for protection against immune challenge by pathogens and transformed cells, while dysregulated antibody production is a hallmark of autoimmune diseases. T follicular helper (Tfh) cells are central to the development of humoral immunity, regulating B-cell maturation, including immunoglobulin class switch recombination and somatic hypermutation, and development of memory B and antibody-producing plasma cells. These events occur as B cells migrate to and differentiate within B cell follicles of secondary lymphoid organs, with this classical program of follicular B cell maturation providing systemic immune protection. Local humoral responses are also necessary for organismal defense against immune challenge. Accordingly, T-dependent B-cell help occurs outside of B-cell follicles, including in non-lymphoid tissues such as the lung, central nervous system, joints, and kidneys. The phenotype and function of T cells that provide humoral protection against pathogens and tumors and conversely promote autoimmunity at the tissue level both overlap with and are distinct from those of canonical Tfh cells. Here, we summarize current knowledge of these tissue T-B helper cells, focusing on their differentiation and function in infection, cancer, and autoimmunity.

Tertiary lymphoid structures (TLSs) are organized aggregates of lymphocytes, myeloid cells, and stromal cells that form at sites of inflammation, providing adaptive immune responses outside of secondary lymphoid organs (SLOs). Found in various pathological conditions—including chronic infections, cancer, organ transplantation, autoimmune diseases, and allergy—the presence of TLSs is linked to potentiation of local immunity. TLSs can be beneficial or detrimental, depending on context, and have been implicated as prognostic for disease severity and therapy response. Architecturally, TLSs resemble SLOs with distinct T and B cell areas supported by fibroblasts that secrete chemokines and cytokines that support immune cells. These structures must be created de novo in non-lymphoid tissues; thus, the steps for TLS formation mimic, but do not completely copy, those of SLO formation. The accumulation of immune cells in tissues in inflammatory settings can initiate remodeling of tissue fibroblasts, leading to TLS formation; this process is common across tissues, although there are tissue- and disease-specific pathways that impact TLS formation in certain contexts. This review will explore the immune-stromal crosstalk in kidney, lung, and skin TLSs across a range of disease settings, highlighting shared as well as tissue-specific mechanisms for TLS formation.

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