Immunological Reviews最新文献

Tertiary lymphoid structures (TLSs) are ectopic lymphoid tissues that form in response to chronic inflammation, such as in autoimmune diseases or cancer. Their presence has been increasingly recognized as a significant factor in determining patient prognosis and response to cancer treatments. The formation and development of TLSs are intricately linked to inflammatory cytokines and chemokines, which can be induced by the innate immune system. The innate immune system serves as the body's first line of defense against pathogens by producing cytokines and chemokines upon the detection of foreign invaders. The interplay between innate immunity and TLSs is multifaceted and involves various components and mechanisms. Here, we focus on three key aspects. First, the involvement of specific innate immune cell types in TLS dynamics; second, the role of innate immune receptors in TLS formation; lastly, the contributions of innate immune effectors to TLS formation and maintenance. By examining these interconnected aspects, we can gain a comprehensive understanding of how innate immunity regulates the formation and function of TLSs in the context of chronic inflammation and cancer. This knowledge not only enhances our understanding of immune responses but also holds potential for developing novel therapeutic strategies targeting TLSs in various pathological conditions.

The thymus is extremely sensitive to insult but also has a remarkable capacity for endogenous repair. However, even though there is continual thymic involution and regeneration in response to everyday insults like stress and infection, profound thymic damage such as ionizing radiation leads to prolonged T cell lymphopenia for which there is currently no therapeutic treatment. We and others have been focusing in recent years on untangling the cellular and molecular mechanisms underlying endogenous thymic regeneration in the hope of being able to exploit them for clinical benefit. To date, multiple molecular mechanisms have been identified that are centered on several distinct cell axes, including interleukin-22 produced by innate lymphoid cells, BMP4 by endothelial cells, and type 2 cytokines from eosinophils, ILCs, and Tregs. Notably, one of the uniting triggers for these pathways of repair centers on the balance of cell death detection. In this review, we will highlight the current state of play with regard to cellular and molecular pathways of regeneration as well as the mechanisms triggering them. We will also highlight recent work that sheds light on the limitations of thymus repair and speculate as to what will be needed for an effective thymus-boosting therapy.

Teleost fish are the most diverse of the vertebrate taxa, made up of over 30,000 different species with diverse life histories, unique immune systems and extreme physiological adaptations. Mammalian immunologists coined primary, secondary and tertiary lymphoid organs based on their developmental, anatomical and functional characteristics and such definitions are often “imposed” on other organisms. For decades, teleost fish were thought to lack lymphoid aggregates beyond those found in the primary lymphoid organs of the thymus and the head-kidney or those found in the spleen (a secondary lymphoid organ). However, over the past two decades several laboratories have uncovered the presence of lymphocyte aggregates in several anatomical locations, mostly mucosal barriers, in teleost fish. These aggregates are difficult to classify as secondary or tertiary lymphoid structures based on the current mammal-based framework. This perspective provides an overview of the latest findings in lymphocyte aggregates in teleost fish and their potential function in adaptive immunity. We proposed a revised definition for tertiary lymphoid organs (TLOs) that is relevant across a wider range of vertebrate taxa and where the lack of baseline SLO makes TLO description and functional characterization even harder. Specifically, we propose experimental paradigms where the “ectopic” nature of TLOs could be ascertained in non-model organisms.

The thymus is crucial for developing immunocompetent T cells expressing T cell receptors (TCRs) capable of responding to foreign antigens while remaining tolerant to self-components. T cell development involves complex interactions with thymic stromal cells, including thymic epithelial cells (TECs). Particularly, T cell selection relies on the coordinated, yet spatially and temporally distinct functions of rare cortical (cTECs) and medullary (mTECs) subtypes. While cTECs are essential for T cell lineage commitment and positive selection, mTECs play a role in central tolerance by eliminating autoreactive cells and promoting regulatory T cell development. Thus, thymic selection refines the TCR repertoire, promoting immune competence to foreign antigens while ensuring tolerance to self. This review focuses on the instructive role of cTECs in positive selection and CD4/CD8 lineage commitment. It further explores recent discoveries on the molecular mechanisms underlying the generation of selective self-peptide–MHC ligands, which are critical for TCR diversification. We also highlight recent findings on TEC heterogeneity and discuss their potential roles in T cell selection. Understanding TEC diversity and their specialized machinery in generating selective ligands reshapes our view of thymic biology and is key to comprehending their influence on peripheral CD4⁺ and CD8⁺ T cell functions.

B-cell epitope specificity on food allergens is highly relevant to understanding both the pathogenesis of IgE and IgG-mediated clinical tolerance after immunotherapy. The molecular binding interactions between the paratopes of antibodies and the epitopes of food allergens drive IgE-crosslinking, the subsequent activation of allergen effector cells, and the symptoms of systemic and life-threatening anaphylaxis. Various characteristics of allergen-specific IgE, such as high affinity and clonal diversity, can contribute to the persistence of food allergy and the severity of anaphylaxis upon allergen exposure. On the other hand, the induction of epitope-specific IgG antibodies in allergic individuals can inhibit IgE binding to food allergens. A subset of these can be neutralizing antibodies that effectively disrupt multiple allergen-IgE interactions to suppress effector responses. This review details the crucial role of epitope specificity and antibody clonality in both the pathogenesis of food allergy and in the development of clinical tolerance.