Current Opinion in Immunology最新文献

Plasma cells correspond to the last stage of B cell differentiation and are professional antibody-secreting cells. While most persist for only few days, some may survive for weeks to years in dedicated survival niches. The determination of plasma cell survival rate seems to rely both on intrinsic and extrinsic factors. Although often opposed, the deterministic and environmental models for plasma cell longevity are certainly overlapping. Understanding the contribution and the regulation of these different factors is paramount to develop better vaccines but also to target malignant plasma cells. Here, we review recent literature highlighting new findings pertaining to plasma cell survival rate, intrinsic regulation of plasma cell persistence and function, as well as the plasma cell/niche dialogue. Moreover, the now well-recognised heterogeneity observed among plasma cells is also discussed.

Immune cells in the tumor microenvironment play a crucial role in cancer prognosis and response to immunotherapy. Recent studies highlight the significance of tumor-infiltrating B cells and tertiary lymphoid structures as markers of favorable prognosis and patient-positive response to immune checkpoint blockers in some types of cancer. Although the presence of germinal center B cells and plasma cells in the tumor microenvironment has been established, determining their tumor reactivity remains challenging. The few known tumor targets range from viral proteins to self and altered self-proteins. The emergence of self-reactive antibodies in patients with cancer, involves the opposing forces of antigen-driven affinity increase and peripheral tolerance mechanisms. Here, B cell tumor antigen specificity and affinity maturation in tumor-directed immune responses in cancer are discussed.

Single-cell RNA sequencing (scRNAseq) and Variable, Diversity, Joining (VDJ) profiling have improved our understanding of B-cells. Recent scRNAseq-based approaches have led to the discovery of intermediate B-cell states, including preplasma cells and pregerminal centre B-cells, as well as unveiling protective roles for B-cells within tertiary lymphoid structures in respiratory infections and cancers. These studies have improved our understanding of transcriptional and epigenetic control of B-cell development and of atypical and memory B-cell differentiation. Advancements in temporal profiling in parallel with transcriptomic and VDJ sequencing have consolidated our understanding of the trajectory of B-cell clones over the course of infection and vaccination. Challenges remain in studying B-cell states across tissues in humans, in relating spatial location with B-cell phenotype and function, in examining antibody isotype switching events, and in unequivocal determination of clonal relationships. Nevertheless, ongoing multiomic assessments and studies of cellular interactions within tissues promise new avenues for improving humoral immunity and combatting autoimmune conditions.

The host immune response against severe acute respiratory syndrome coronavirus 2 includes the induction of a group of natural antiviral cytokines called interferons (IFNs). Although originally recognized for their ability to potently counteract infections, the mechanistic functions of IFNs in patients with varying severities of coronavirus disease 2019 (COVID-19) have highlighted a more complex scenario. Cellular and molecular analyses have revealed that timing, location, and subtypes of IFNs produced during severe acute respiratory syndrome coronavirus 2 infection play a major role in determining disease progression and severity. In this review, we summarize what the COVID-19 pandemic has taught us about the protective and detrimental roles of IFNs during the inflammatory response elicited against a new respiratory virus across different ages and its longitudinal consequences in driving the development of long COVID-19.

Recognition of antigens by T cell receptors (TCRs) and B cell receptors (BCRs) is a key step in lymphocyte activation. T and B cells mediate adaptive immune responses, which protect us against infections and provide immunological memory, and also, in some instances, drive pathogenic responses in autoimmune diseases. TCRs and BCRs are encoded within loci that are known to be genetically diverse. However, the extent and functional impact of this variation, both in humans and model animals used in immunological research, remain largely unknown. Experimental and genetic evidence has demonstrated that the complementarity determining regions 1 and 2 (HCDR1 and HCDR2), encoded by the variable (V) region of TCRs and BCRs, also often make critical contacts with the targeted antigen. Thus, knowledge about allelic variation in the genes encoding TCRs and BCRs is critically important for understanding adaptive immune responses in outbred populations and to define responder and non-responder phenotypes.

The essential and redundant functions of human type I and II interferons (IFNs) have been delineated over the last three decades by studies of patients with inborn errors of immunity or their autoimmune phenocopies, but much less is known about type III IFNs. Patients with cells that do not respond to type III IFNs due to inherited IL10RB deficiency display no overt viral disease, and their inflammatory disease phenotypes can be explained by defective signaling via other interleukine10RB-dependent pathways. Moreover, patients with inherited deficiencies of interferon-stimulated gene factor 3 (ISGF-3) (STAT1, STAT2, IRF9) present viral diseases also seen in patients with inherited deficiencies of the type I IFN receptor (IFNAR1/2). Finally, patients with autoantibodies neutralizing type III IFNs have no obvious predisposition to viral disease. Current findings thus suggest that type III IFNs are largely redundant in humans. The essential functions of human type III IFNs, particularly in antiviral defenses, remain to be discovered.

Effective high-affinity, long-term humoral immunity requires T cell help provided by a subset of differentiated CD4⁺ T cells known as T follicular helper (Tfh) cells. Classically, Tfh cells provide contact-dependent help for the generation of germinal centers (GCs) in secondary lymphoid organs (SLOs). Recent studies have expanded the conventional definition of Tfh cells, revealing new functions, new descriptions of Tfh subsets, new factors regulating Tfh differentiation, and new roles outside of SLO GCs. Together, these data suggest that one Tfh is not equivalent to another, helping redefine our understanding of Tfh cells and their biology.

Lambda interferons (IFNλs), also termed type III interferons (IFNs) or interleukins-28/29, have been in the shadow of type I IFNs for a long time. Their common induction mechanisms and signalling cascades with type I IFNs have made difficult the unwinding of their unique nonredundant functions. However, this is now changing with mounting evidence supporting a major role of IFNλs as a specialized antiviral defense system in the body, mediating protection at mucosal barrier surfaces while limiting immunopathology.

Here, we review the latest progress on the complex activities of IFNλs in the respiratory tract, focusing on their multiple effects in IFNλ receptor-expressing cells, the modulation of innate and adaptive immune responses in the context of infections and respiratory diseases, and their similarities and differences with type I IFNs. We also discuss their potential in therapeutic applications and the most recent developments in that direction.

Interferons (IFNs) are an integral component of the host innate immune response during viral infection. Recent advances in the study of type I and III IFNs suggest that though both types counteract viral infection, type III IFNs act predominantly at epithelial barrier sites, while type I IFNs drive systemic responses. The dynamics and specific roles of type I versus III IFNs have been studied in the context of infection by a variety of enteric pathogens, including reovirus, rotavirus, norovirus, astrovirus, and intestinal severe acute respiratory syndrome coronavirus 2, revealing shared patterns of regulatory influence. An important role for the gut microbiota, including the virome, in regulating homeostasis and priming of intestinal IFN responses has also recently emerged.

The composition and quantity of food we eat have a drastic impact on the development and function of immune responses. In this review, we highlight defined nutritional interventions shown to enhance antitumor immunity, including ketogenic, low-protein, high-fructose, and high-fiber diets, as well as dietary restriction. We propose that incorporating such nutritional interventions into immunotherapy protocols has the potential to increase therapeutic responsiveness and long-term tumor control in patients with cancer.