Current Opinion in Immunology最新文献

Since the discovery of Toll and Toll-like receptors (TLRs) in the 90s, an extensive body of research has been performed to determine how Pattern Recognition Receptors (PRRs) recognise ‘ligands’ and signal. The families of PRRs now include membrane and cytosolic proteins, which broadly signal by forming large protein platforms or supramolecular organising centres (SMOCs). The concept of SMOC-driven signalling has led to the development of a set of assumptions, particularly for TLRs, based on experimental data, to explain the physiological consequences of PRR activation. Recent research suggests that at least some of these assumptions should be reconsidered, especially as many of these receptors are important therapeutic targets for drug development, so understanding the mechanisms by which they signal is critical.

The microbiome regulates mammalian immune responses from early life to adulthood. Antigen presentation, orchestrating these responses, integrates commensal and pathogenic signals. However, the temporal and spatial specificity of microbiome impacts on antigen presentation and downstream tolerance versus inflammation remain incompletely understood. Herein, we review the influences of antigen presentation of microbiome-related epitopes on immunity; impacts of microbiome-based modulation of antigen presentation on innate and adaptive immune responses; and their ramifications on homeostasis and immune-related disease, ranging from auto-inflammation to tumorigenesis. We highlight mechanisms driving these influences, such as ‘molecular mimicry’, in which microbiome auto-antigen presentation aberrantly triggers an immune response driving autoimmunity or influences conferred by microbiome-derived metabolites on antigen-presenting cells in inflammatory bowel disease. We discuss unknowns, controversies, and challenges associated with the study of microbiome regulation of antigen presentation while demonstrating how increasing knowledge may contribute to the development of microbiome-based therapeutics modulating immune responses in a variety of clinical contexts.

T follicular helper (Tfh) cells help direct the production of antibodies by B cells. In addition to promoting antibody responses to vaccination and infection, Tfh cells have been found to mediate antibody production to food antigens. Work over the past decade has delineated the specific phenotypes of Tfh cells that induce antibodies to food while also clarifying the divergent Tfh cell requirement for different food-specific antibody isotypes. Furthermore, Tfh and antibody responses to food can occur at multiple barrier sites — namely, skin, airway, and gut. Depending on the context of food antigen exposure, the immune response to food at these sites can be protective, as in the case of tolerance or immunotherapy, or pathogenic, as in the case of allergy. This review will highlight recent advances in our understanding of how Tfh cells promote antibodies to food as well as future avenues for continued discovery.

In tumors, immune cells organize into networks of different sizes and composition, including complex tertiary lymphoid structures and recently identified networks centered around the chemokines CXCL9/10/11 and CCL19. New commercially available highly multiplexed microscopy using cyclical RNA in situ hybridization and antibody-based approaches have the potential to establish the organization of the immune response in human tissue and serve as a foundation for future immunology research.

Signal integration is central to a causal understanding of appropriately scaled inflammatory responses. Here, we discuss recent progress in our understanding of the stimulus–response linkages downstream of pro-inflammatory inputs, with special attention to (1) the impact of cell state on the specificity of evoked gene expression and (2) the critical role of the spatial context of stimulus exposure. Advances in these directions are emerging from new tools for inferring cell–cell interactions and the activities of cytokines and transcription factors in complex microenvironments, enabling analysis of signal integration in tissue settings. Building on data-driven elucidation of factors driving inflammatory outcomes, mechanistic modeling can then contribute to a quantitative understanding of regulatory events that balance protective versus pathological inflammation.