Immunological Reviews最新文献

Bacterial and viral infections initiate classical type-1 immune responses. Together, pathogen-specific CD8+ cytotoxic T cells, CD4+ T helper 1 (Th1) cells, and classically activated macrophages cooperate to kill and eliminate infected cells. After pathogen clearance, the type-1 response resolves. Resolution of a classical inflammatory response is critical to host health. The importance of limiting inflammation after pathogen clearance is evident from the association of chronic type-1 inflammation with diverse diseases ranging from inflammatory bowel disease, chronic obstructive pulmonary disease, diabetes, and Alzheimer's disease [1-4].

While optimal for protection against viruses and bacteria, type-1 inflammation is not effective at controlling large extracellular helminths. These worms are orders of magnitude larger than viruses and bacteria, preventing classical macrophage clearance and phagocytosis of infected cells. If such a response was mounted, the inability of the host to clear the worms would lead to persistent type-1 inflammation. As stated above, such persistence of type-1 inflammation would ultimately be detrimental to the host. To avoid this, mammals have evolved the ability to mount a type-2 immune response to combat extracellular worm infections [5, 6]. Unlike type-1-driven immunity, which is focused on the direct killing and clearance of infected cells, type-2 inflammation is centered on the recruitment of innate immune cells to the site of infection; limiting nutrient availability during feeding by walling off the attachment site (wound healing response); and clearing of the worm through mucus production and smooth muscle contraction (weep and sweep). Also important, type-2 inflammation suppresses classical type-1 inflammation. These processes occur in multiple tissues infected by these parasites including the lung.

However, type-2 inflammation can also be detrimental to the host. If a type-2 response is evoked in the presence of a normally inert protein (allergen), it can be associated with allergic disease. In the context of the lung, type-2 inflammation to allergens is defined as allergic asthma [7]. Interestingly, the pathobiology associated with soil-transmitted helminth infection, as they migrate through the lung, closely resembles the pathobiology seen in the lungs of asthmatics. In both cases, the classical hallmarks of type-2 inflammation are evident: eosinophilia, goblet cell hyperplasia and mucus production, and elevated immunoglobulin-E, IgG1, and IgG4.

These classical hallmarks of type-2 inflammation are driven in large part by the production of type-2 cytokines—interleukin-4, IL-5, and IL-13 [8]. IL-4 is critical for the class-switching of B cells to IgE and IgG1. IL-5 mobilizes eosinophils from the bone marrow. IL-13 drives both the induction of goblet cell hyperplasia and mucus production as well as smooth muscle contractility. The critical

The primary features of the alpha-gal syndrome (AGS) are (i) The IgE ab that are causally related to anaphylaxis with infusions of Cetuximab are specific for galactose alpha-1,3-galactose. (ii) In the USA, this IgE ab is induced by bites of the tick Amblyomma americanum. (iii) The anaphylactic reactions to food derived from non-primate mammals are delayed in onset by three to five hours. A further important fact is that all humans make a “natural” response to alpha-gal which includes IgM, IgG, and IgA, but not IgE. The clinical features of AGS are recognized in many parts of the world, but different species of ticks are involved. The immune response to tick bites includes T cells specific for tick protein, while IgE producing B cells appear to be derived from B cells specific for IgM or IgG. With repeated tick bites, the T cells develop a strong Th2 signal with IL-4 and IL-13 This obviously relates to IgE production, but may also be relevant to itching after tick bites which can last for weeks. The current hypothesis about the cause of the delayed reactions is based on the time that it takes to digest glycolipids from meat to LDL. The management of AGS symptoms is based on the avoidance of food derived from mammals; however, the only thing that can allow IgE to decrease is avoidance of tick bites.

The thymus is a primary lymphoid organ for generating a diverse yet self-tolerant T cell repertoire. Among the thymic stromal cells that create the thymic microenvironment, thymic epithelial cells (TECs) have received the most attention because of their distinctive functions in the repertoire selection of T cells. Other types of thymic stromal cells, such as fibroblasts and endothelial cells, have been less studied, and thus their thymus-specific nature and functions remain unclear. Recent advances in single-cell technologies, multicolor flow cytometry, and sophisticated mouse models have enabled the identification not only of TECs but also of non-TEC stromal cell diversity and the characterization of these cell subpopulations. This review provides a state-of-the-art overview of the thymic microenvironment, focusing on the development and functional diversity of TECs and non-TEC stromal cells. In particular, the recently discovered role of non-TEC stromal cells in thymic organogenesis, T cell selection, and involution and regeneration of the postnatal thymus is highlighted.

Type-2 inflammation is driven by the production of canonical type-2 cytokines IL-4, IL-5, and IL-13. Type-2 cytokines promote mucus production, innate immune cell recruitment, and smooth muscle contractility in mucosal tissues. These hallmarks of type-2 inflammation are important contributors to the weep-and-sweep responses observed in the lung and intestine after epithelial insults. While these type-2 cytokines are generated by a number of innate and adaptive immune cells, group 2 innate lymphoid cells (ILC2) are key early producers of these cytokines and are critical in shaping immune responses in the lung. This review summarizes the role of ILC2 in the lung with specific emphasis on their origins as part of the gut-lung axis, their heterogeneity with respect to unique identities of circulating and tissue resident ILC2 populations, and how these relatively rare immune cells can significantly impact the course of pulmonary disease. We also explore factors that influence ILC2 behavior with respect to activation, migration, and communication with their environment.

The thymus exhibits constitutive activation of nearly all major inflammatory pathways, including sterile MyD88-dependent signaling and interferon production by mTECs, the presence of cellular and molecular components of type 1, type 2, and type 3 responses, as well as sustained B cell activation. The reasons for the existence of such a complex constitutively active inflammatory network at the site of T cell development—where the initial pathogen encounter is unlikely—have remained enigmatic. We propose that this inflammatory thymic ‘ecosystem’ has evolved to promote immunological tolerance to ‘inflammatory self’—endogenous molecules absent from most peripheral tissues at steady state but upregulated during pathogen invasion. The spatial and temporal overlap with pathogen presence makes the discrimination of the inflammatory self from pathogen-derived molecules a unique challenge for the adaptive immune system. The frequent occurrence of diseases associated with autoantibodies against proinflammatory cytokines underscores the persistent risk of these molecules being misidentified as foreign. Their abundant representation in the thymus, therefore, is likely to be critical for maintaining tolerance. This review explores current insights into the thymic inflammatory network, its cellular and molecular constituents, and their role in the induction of T cell tolerance.

Thymic dendritic cells (DCs) are critical mediators of central tolerance, cooperating with medullary thymic epithelial cells (mTECs) and B cells to establish T-cell self-tolerance to the proteome. The DC compartment is highly heterogeneous and is comprised of three major subsets, plasmacytoid dendritic cells (pDCs) and two conventional dendritic cell (cDC) subsets, cDC1 and cDC2. Thymic cDC1 and cDC2 arise from distinct progenitors and access the thymus at different stages of their differentiation, but both become activated by cellular and secreted cues received within the sterile thymus environment. Activated cDC1s and cDC2s have been implicated in presenting distinct types of self-antigens to induce central tolerance. Thus, understanding how the distinct cDC subsets are regulated within the thymus environment will provide important insights into mechanisms governing self-tolerance. Furthermore, the thymic DC compartment undergoes age-associated compositional and transcriptional changes that likely impact the efficiency and quality of central tolerance established over the lifespan. Here, we review recent findings from our lab and others on mechanisms regulating thymic DC activation, the distinct roles of thymic DC subsets in central tolerance, and age-associated changes in thymic DCs that could impact T-cell selection.

The major histocompatibility complex class-I related protein, MR1, is an evolutionarily conserved antigen presenting molecule that binds and displays organic metabolites to T cells, including mucosal associated invariant T (MAIT) cells and diverse MR1-restricted T cells (MR1T). Structural studies have elucidated how MR1 can accommodate a range of chemical scaffolds that arise from foreign, synthetic, and self-metabolites, although the full spectrum of metabolites that MR1 presents remains unclear. Presently, MAIT and MR1T cell recognition of MR1-antigen complexes represents a new immune recognition paradigm and is emerging as a critical player in protective immunity, aberrant immunity, tumor immunity, and tissue repair. Moreover, the limited allelic variation of MR1 makes it an attractive therapeutic target. This review will address the unique features and capability of the MR1 molecule to display several classes of small molecules for T cell surveillance. We will also address the molecular basis underlying MAIT and MR1T TCR recognition of MR1-binding ligands.