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Interleukin-10 (IL-10) is an anti-inflammatory cytokine with important immunoregulatory functions. It is primarily secreted by antigen-presenting cells such as activated T-cells, monocytes, B-cells and macrophages. In biologically functional form, it exists as a homodimer that binds to tetrameric heterodimer IL-10 receptor and induces downstream signaling. IL-10 is associated with survival, proliferation and anti-apoptotic activities of various cancers such as Burkitt lymphoma, non-Hodgkins lymphoma and non-small scell lung cancer. In addition, it plays a central role in survival and persistence of intracellular pathogens such as Leishmania donovani , Mycobacterium tuberculosis and Trypanosoma cruzi inside the host. The signaling mechanisms of IL-10 cytokine are not well explored and a well annotated pathway map has been lacking. To this end, we developed a pathway resource by manually annotating the IL-10 induced signaling molecules derived from literature. The reactions were categorized under molecular associations, activation/inhibition, catalysis, transport and gene regulation. In all, 37 molecules and 76 reactions were annotated. The IL-10 signaling pathway can be freely accessed through NetPath, a resource of signal transduction pathways previously developed by our group.

Background Dendritic cells (DCs) play a crucial role in immunity. Research on monocyte‐derived DCs (Mo‐DCs) cancer vaccines is in progress despite limited success in clinical trials. This study focuses on Mo‐DCs generated from prostate cancer (PCA) patients, comparing them with DCs from healthy donors (HD‐DCs). Methods Mo‐DCs were isolated from PCA patient samples, and their phenotype was compared to HD‐DCs. Key parameters included monocyte count, CD14 expression, and the levels of maturation markers (HLA‐DR, CD80, CD86) were assessed. Results PCA samples exhibited a significantly lower monocyte count and reduced CD14 expression compared to healthy samples (p ⟨ 0.0001). Additionally, PCA‐DCs expressed significantly lower levels of maturation markers, including HLA‐DR, CD80, and CD86, when compared to HD‐DCs (p = 0.123, p = 0.884, and p = 0.309, respectively). Conclusion The limited success of DC vaccines could be attributed to impaired phenotypic characteristics. These observations suggest that suboptimal characteristics of Mo‐DCs generated from cancer patient blood samples might contribute to the limited success of DC vaccines. Consequently, this study underscores the need for alternative strategies to enhance the features of Mo‐DCs for more effective cancer immunotherapies.

[This corrects the article DOI: 10.3389/fimmu.2022.946456.].

Aging has profound effects on the immune system, including thymic involution, reduced diversity of the T cell receptor repertoire, reduced effector T cell and B cell function and chronic increase of proinflammatory cytokine production by innate immune cells. The precise effects of aging on conventional dendritic cells (cDC), the main antigen presenting cells of the immune system, however, are not well understood. We found that in aged mice the number of cDC in the spleen and lymph nodes remained stable, whereas the number of cDC in the lungs increased with age. Whereas cDC in mice showed similar cycling kinetics in all organs tested, cDC reconstitution by aged bone marrow precursors was relatively higher than that of their young counterparts. With the exception of CD86, young and aged cDC did not differ in their expression of co‐stimulatory molecules at steady state. Most toll‐like receptor (TLR) ligands induced comparable upregulation of co‐stimulatory molecules CD40, CD86 and B7H1 on young and aged cDC, whereas TLR2 and TLR5 stimulation resulted in reduced upregulation of CD80 and CD86 on aged cDC in vitro. In vivo, influenza infection‐induced upregulation of CD86, but not other co‐stimulatory molecules, was lower in aged DC. Young and aged DC were equally capable of direct and cross presentation of antigens in vitro. Transcriptome analysis did not reveal any significant difference between young and aged cDC. These data show that unlike T and B cells, the maintenance of cDC throughout the life of a healthy animal is relatively robust during the aging process.

Over the last 15 years, the inducible T cell co-stimulator (ICOS) has been implicated in various immune outcomes, including the induction and regulation of Th1, Th2, and Th17 immunity. In addition to its role in directing effector T cell differentiation, ICOS has also been consistently linked with the induction of thymus-dependent (TD) antibody (Ab) responses and the germinal center (GC) reaction. ICOS co-stimulation, therefore, appears to play a complex role in dictating the course of adaptive immunity. In this article, we summarize the initial characterization of ICOS and its relationship with the related co-stimulatory molecule CD28. We then address the contribution of ICOS in directing an effector T cell response, and ultimately disease outcome, against various bacterial, viral, and parasitic infections. Next, we assess ICOS in the context of TD Ab responses, connecting ICOS signaling to follicular helper T cell differentiation and its role in the GC reaction. Finally, we address the link between ICOS and human autoimmune disorders and evaluate potential therapies aiming to mitigate disease progression by modulating ICOS signaling.

Human leukocyte antigen genes have been shown to have the strongest association with autoimmune disease (AD). However, non-HLA genes would be risk factors of AD. Many genes encoding proteins that are related to T- and B-cell function have been identified as susceptibility genes of systemic lupus erythematosus (SLE). In this study, we explored the correlation between SLE and the genetic polymorphisms of co-stimulatory/co-inhibitory molecules, including CTLA4, CD28, ICOS, PDCD1, and TNFSF4. We found that there were nine single-nucleotide polymorphisms (SNPs) associated with SLE, namely, rs11571315 (TT vs. CT vs. CC: p < 0.001; TT vs. CT: p = 0.001; p = 0.005; TT vs. CT +CC: p < 0.001; TT+CT vs. CC: p = 0.032), rs733618 (CC vs. CT vs. TT: p = 0.002; CC vs. CT: p = 0.001; CC vs. TT: p = 0.018; CC vs. CT + TT: p = 0.001), rs4553808 (AA vs. AG: p < 0.001), rs62182595 (GG vs. AG vs. AA: p < 0.001; GG vs. AG: p < 0.001; GG vs. AG+AA: p < 0.001), rs16840252 (CC vs. CT vs. TT: p < 0.001; CC vs. CT: p < 0.001; CC vs. CT + TT: p < 0.001), rs5742909 (CC vs. CT: p = 0.027; CC vs. CT + TT: p = 0.044), rs11571319 (GG vs. AG vs. AA: p < 0.001, GG vs. AG: p < 0.001; GG vs. AG+AA: p < 0.001), rs36084323 (CC vs. CT vs. TT: p = 0.013, CC vs. TT: p = 0.004; CC vs. CT + TT: p = 0.015; CC +CT vs. TT: p = 0.015), and rs1234314 (CC vs. CG vs. GG: p = 0.005; CC vs. GG: p=0.004; CC+ CG vs. GG: p=0.001), but not in CD28 and ICOS by using the chi-square test. Additionally, rs62182595 and rs16840252 of CTLA and rs1234314 and rs45454293 of TNFSF4 were also associated with SLE in haplotypes. These SLE-related SNPs also had an association with several diseases. It was indicated that these SNPs may play an important role in immune regulation and pathogenic mechanisms.

Inhibition of Bruton’s Tyrosine Kinase (BTKi) is now viewed as a promising next-generation B-cell-targeting therapy for autoimmune diseases including multiple sclerosis (MS). Surprisingly little is known; however, about how BTKi influences MS disease-implicated functions of B cells. Here, we demonstrate that in addition to its expected impact on B-cell activation, BTKi attenuates B-cell:T-cell interactions via a novel mechanism involving modulation of B-cell metabolic pathways which, in turn, mediates an anti-inflammatory modulation of the B cells. In vitro, BTKi, as well as direct inhibition of B-cell mitochondrial respiration (but not glycolysis), limit the B-cell capacity to serve as APC to T cells. The role of metabolism in the regulation of human B-cell responses is confirmed when examining B cells of rare patients with mitochondrial respiratory chain mutations. We further demonstrate that both BTKi and metabolic modulation ex vivo can abrogate the aberrant activation and costimulatory molecule expression of B cells of untreated MS patients. Finally, as proof-of-principle in a Phase 1 study of healthy volunteers, we confirm that in vivo BTKi treatment reduces circulating B-cell mitochondrial respiration, diminishes their activation-induced expression of costimulatory molecules, and mediates an anti-inflammatory shift in the B-cell responses which is associated with an attenuation of T-cell pro-inflammatory responses. These data collectively elucidate a novel non-depleting mechanism by which BTKi mediates its effects on disease-implicated B-cell responses and reveals that modulating B-cell metabolism may be a viable therapeutic approach to target pro-inflammatory B cells.

HAb18G/CD147, a glycoprotein of the immunoglobulin super‐family (IgSF), is a T cell activation‐associated molecule. In this report, we demonstrated that HAb18G/CD147 expression on both activated CD4+ and CD8+ T cells was up‐regulated. In vitro cross‐linking of T cells with an anti‐HAb18G/CD147 monoclonal antibody (mAb) 5A12 inhibited T cells proliferation upon T cell receptor stimulation. Such co‐stimulation inhibited T cell proliferation by down‐regulating the expression of CD25 and interleukin‐2 (IL‐2), decreased production of IL‐4 but not interferon‐γ. Laser confocal imaging analysis indicated that HAb18G/CD147 was recruited to the immunological synapse (IS) during T cell activation; triggering HAb18G/CD147 on activated T cells by anti‐HAb18G/CD147 mAb 5A12 strongly dispersed the formation of the IS. Further functional studies showed that the ligation of HAb18G/CD147 with mAb 5A12 decreased the tyrosine phosphorylation and intracellular calcium mobilization levels of T cells. Through docking antibody–antigen interactions, we demonstrated that the function of mAb 5A12 is tightly dependent on its specificity of binding to N‐terminal domain I, which plays pivotal role in the oligomerization of HAb18G/CD147. Taken together, we provide evidence that HAb18G/CD147 could act as a co‐stimulatory receptor to negatively regulate T cell activation and is functionally linked to the formation of the IS.

This review explores some of the complex mechanisms underlying antitumor T-cell response, with a specific focus on the balance and cross-talk between selected co-stimulatory and inhibitory pathways. The tumor microenvironment (TME) fosters both T-cell activation and exhaustion, a dual role influenced by the local presence of inhibitory immune checkpoints (ICs), which are exploited by cancer cells to evade immune surveillance. Recent advancements in IC blockade (ICB) therapies have transformed cancer treatment. However, only a fraction of patients respond favorably, highlighting the need for predictive biomarkers and combination therapies to overcome ICB resistance. A crucial aspect is represented by the complexity of the TME, which encompasses diverse cell types that either enhance or suppress immune responses. This review underscores the importance of identifying the most critical cross-talk between inhibitory and co-stimulatory molecules for developing approaches tailored to patient-specific molecular and immune profiles to maximize the therapeutic efficacy of IC inhibitors and enhance clinical outcomes.

Targeting PD-L1 via monospecific antibodies has shown durable clinical benefits and long-term remissions where patients exhibit no clinical cancer signs for many years after treatment. However, the durable clinical benefits and long-term remissions by anti-PD-L1 monotherapy have been limited to a small fraction of patients with certain cancer types. Targeting PD-L1 via bispecific antibodies (referred to as anti-PD-L1-based bsAbs) which can simultaneously bind to both co-inhibitory and co-stimulatory molecules may increase the durable antitumor responses in patients who would not benefit from PD-L1 monotherapy. A growing number of anti-PD-L1-based bsAbs have been developed to fight against this deadly disease. This review summarizes recent advances of anti-PD-L1-based bsAbs for cancer immunotherapy in patents and literatures, and discusses their anti-tumor efficacies in vitro and in vivo. Over 50 anti-PD-L1-based bsAbs targeting both co-inhibitory and co-stimulatory molecules have been investigated in biological testing or in clinical trials since 2017. At least eleven proteins, such as CTLA-4, LAG-3, PD-1, PD-L2, TIM-3, TIGIT, CD28, CD27, OX40, CD137, and ICOS, are involved in these investigations. Twenty-two anti-PD-L1-based bsAbs are being evaluated to treat various advanced cancers in clinical trials, wherein the indications include NSCLC, SNSCLC, SCLC, PDA, MBNHL, SCCHN, UC, EC, TNBC, CC, and some other malignancies. The released data from clinical trials indicated that most of the anti-PD-L1-based bsAbs were well-tolerated and showed promising antitumor efficacy in patients with advanced solid tumors. However, since the approved and investigational bsAbs have shown much more significant adverse reactions compared to PD-L1 monospecific antibodies, anti-PD-L1-based bsAbs may be further optimized via molecular structure modification to avoid or reduce these adverse reactions.