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关键词： MHC-I epitope   Pioneer Translation Products   bi-directional transcripts   bi-directional translation   reverse strand antigenic peptides  

摘要： Antisense transcripts play an important role in generating regulatory non-coding RNAs but whether these transcripts are also translated to generate functional peptides remains poorly understood. In this study, RNA sequencing and six-frame database generation were combined with mass spectrometry analysis of peptides isolated from polysomes to identify Nascent Pioneer Translation Products (Na-PTPs) originating from alternative reading frames of bi-directional transcripts. Two Na-PTP originating peptides derived from antisense strands stimulated CD8+ T cell proliferation when presented to peripheral blood mononuclear cells (PBMCs) from nine healthy donors. Importantly, an antigenic peptide derived from the reverse strand of two cDNA constructs was presented on MHC-I molecules and induced CD8+ T cell activation. The results demonstrate that three-frame translation of bi-directional transcripts generates antigenic peptide substrates for the immune system. This discovery holds significance for understanding the origin of self-discriminating peptide substrates for the major histocompatibility class I (MHC-I) pathway and for enhancing immune-based therapies against infected or transformed cells.

摘要： Invasive C. albicans infections result in high mortality rates. While IL-1 is important to combat C. albicans infections, the underlying mechanisms remain unclear. Using global and conditional Il1r1 knockouts in mice, here we show that IL-1R signaling in non-hematopoietic cells in the kidney and brain is crucial for a protective response. In the kidney, endothelial IL-1R contributes to fungal clearance independent of neutrophil recruitment, while IL-1R in hematopoietic cells is dispensable. IL-1R signaling indirectly recruits neutrophils and monocytes in the brain by regulating chemokines and adhesion molecules. Single-nucleus-RNA-sequencing data implicates excessive metabolic activity and oxidative phosphorylation across all cell types in the kidney of Il1r1-deficient mice within a few hours upon infection, with associated, localized hypoxia at infection foci. Lastly, we find that hypoxia promotes fungal growth and pathogenicity. In summary, our results show that IL-1R-signaling in non-hematopoietic cells is required to prevent fatal candidiasis by inhibiting a metabolic shift, including excessive oxidative phosphorylation and hypoxia.

关键词： ankylosing spondylitis   CREG1   IL33   pathological new bone formation   TREM2(+) macrophages  

摘要： Pathological new bone formation is the main cause of disability in ankylosing spondylitis (AS), and so far, it lacks a targeted therapy. Macrophages are central orchestrators of inflammation progression and tissue remodeling, but their contribution to pathological new bone formation has largely not been explored. Here, it is identified that TREM2(+) macrophages predominated within the sites of new bone formation and adjacent to osteogenic precursor cells. In vivo, both depletion of macrophages and knockout of Trem2 significantly reduced pathological new bone formation in a collagen antibody-induced arthritis (CAIA) model. Specifically, TREM2(+) macrophages promoted osteogenic differentiation of ligament-derived progenitor cells (LDPCs) by secreting CREG1, a secretory glycoprotein involved in cell differentiation and normal physiology. CREG1-IGF2R-PI3K-AKT signaling pathway is involved in TREM2(+) macrophage-mediated pathological new bone formation. In addition, it is found that IL-33 promoted TREM2(+) macrophage differentiation through phosphorylation of STAT6. Targeting the above signalings alleviated new bone formation in the CAIA model. The findings highlight the critical role of IL-33-induced TREM2(+) macrophages in pathological new bone formation and provide potential therapeutic targets for halting spinal ankylosis in AS.

关键词： B cell development   CD25   class switch recombination   germinal centers  

摘要： The cytokine IL-2 plays a pivotal role in the immune system, specifically in the proliferation of T, B, and NK cells. The alpha subunit of the IL-2 receptor, IL-2Rα (CD25), is known to regulate the expansion and differentiation of T lymphocytes. CD25 is also expressed in developing B cells; however, its B cell intrinsic role remains undefined. We generated a mouse model with a B cell-specific deletion of CD25 to ascertain its role in B cell development and function. Unexpectedly, we found that the loss of CD25 had no impact on B cell development, homeostasis, or immune response to model antigens. Additionally, while CD25 expression was upregulated in activated splenic B cells, its absence did not affect class switch recombination in vitro or in vivo. We conclude that in contrast to its critical role in T cell differentiation and function, and despite its expression in developing and activated B cells, CD25 does not have any significant role in B cell development and adaptive immune functions.

关键词： Tuberculosis   Latent tuberculosis infection   Biomarker   Diagnosis   IL-8   IL-33   IL-18  

摘要： PurposesA leading cause of death from infectious diseases worldwide is tuberculosis (TB), and it often arises from latent infection. New diagnostic tests for latent tuberculosis infection (LTBI) are needed. Therefore, this study aimed to identify novel biomarker signatures in whole human blood to distinguish between active tuberculosis (ATB) and *** LEGENDplex (TM) kits were used to evaluate the secretion levels of 20 cytokines triggered by ESAT-6/CFP10 antigen in whole blood of ATB, LTBI, and healthy controls, and to search for cytokine combinations utilized to distinguish between ATB and ***-8, IL-18, IL-33, MCP-1, MIG (baseline levels);IL-8, IL-33, IL-1 beta, MCP-1, MIG, IL-10, I-TAC (ESAT-6/CFP10-stimulated levels);and IL-18, IL-33, IL-1 beta, IL-10, TNF-alpha (ESAT-6/CFP10-stimulated minus baseline levels) had the potential to distinguish ATB from LTBI. Our data shows that the sensitivity and specificity of targeted IL-8 and IL-33 distinguishing between ATB and LTBI were 83.3% and 93.75%, and the diagnostic accuracy was 89.28%, and the sensitivity and specificity of targeted IL-18 and IL-33 distinguishing between ATB and LTBI were 91.67% and 81.25%, with the diagnostic accuracy was 85.71%.ConclusionsOur data suggest that IL-8/IL-33 and IL-33/IL-18 together can be utilized as immunological markers to differentiate between LTBI and ATB. A novel TB diagnostic protocol was established, offering novel perspectives to create better tests.

关键词： HDFlu   Influenza vaccine   MF59Flu   antibody   chemokines   cytokines   older adults  

摘要： BACKGROUND:Antibody responses to MF59-adjuvanted (MF59Flu) and high-dose (HDFlu) influenza vaccines have been well-characterized in older adults, yet corresponding cellular immune response data remain limited. METHODS:Blood samples were collected from 106 MF59Flu recipients and 112 HDFlu recipients at four time points: before vaccination (Day 0), and on Days 1, 8, and 28 post-vaccination. Antibody responses were assessed in serum samples using a hemagglutination inhibition assay. Eight pro-inflammatory cytokines and chemokines, including IFN-α2a, IFN-γ, IP-10, MCP-1, MIP-1α, IL-1β, IL-6, and IL-8, were quantified from PBMCs using a multiplex assay. Associations between cytokine/chemokine secretion levels and antibody responses were examined, along with the effect of sex, age, body mass index (BMI), and cytomegalovirus infection status. RESULTS:Age was positively correlated with IL-8 levels on Day 1 (r = 0.24, p < 0.001) and the change in IL-8 levels from Day 0 to Day 1 (r = 0.16, p = 0.021). Notably, the change in IL-8 levels was negatively associated with Day 28 HAI titers (r = -0.15, p = 0.026). Causal mediation analysis demonstrated that IL-8 exerted significant causal mediation effects on antibody responses at both Day 8 (p = 0.046) and Day 28 (p = 0.0045). No significant effects of other cytokines and chemokines, vaccine type, sex, or BMI on antibody responses were observed. CONCLUSION:Our findings underscore IL-8 as a potential mediator of antibody responses to influenza vaccination in older adults, suggesting that IL-8 inhibition could serve as a molecular intervention to improve antibody responses in this high-risk population.

关键词： interleukin 10   cancer immunotherapy   pegylated IL-10   IL-10 fusion proteins and delivery systems   engineered IL-10 variants  

摘要： Cytokine-based immunotherapy has revolutionized cancer treatment;however, its efficacy remains limited by insufficient tumor immune infiltration and resistance mechanisms within the tumor microenvironment. Among these cytokines, interleukin-10 (IL-10) has garnered significant interest due to its dual roles in cancer biology, exhibiting both tumor-suppressive and tumor-promoting properties. Despite these contrasting effects, sustained IL-10 signaling has emerged as a promising strategy for cancer immunotherapy, as it effectively activates and expands tumor-specific cytotoxic CD8+ T cells while concurrently mitigating tumor-associated inflammation. This unique anti-tumor multifunctionality positions IL-10 as a compelling candidate for next-generation cancer immunotherapy, particularly in combination regimens with immune checkpoint inhibitors or other immunomodulatory agents. To harness its anti-tumor therapeutic potential and enhance clinical applicability, various bioengineering strategies are being actively explored, with PEGylation serving as a key advancement in improving IL-10's stability, half-life, and pharmacokinetics. Furthermore, innovative delivery platforms, including fusion proteins, bispecific constructs, and nanoparticle-based formulations, are being developed to optimize tumor-specific targeting and therapeutic efficacy. This review critically examines recent progress, ongoing challenges, and emerging advancements in IL-10-directed cancer immunotherapy, highlighting the need for refined delivery strategies, enhanced intratumoral targeting, and synergistic combination approaches. Continued research and technological innovation are imperative to unlock the full therapeutic potential of IL-10, paving the way for more effective and durable cancer immunotherapies across diverse malignancies.

关键词： IL-18   immune checkpoint inhibitor   PD-1   NK cells   cDC1  

摘要： The success of cancer immunotherapy depends on the effective coordination of innate and adaptive immunity. We previously reported that IL-18 potentiates the therapeutic effects of immune checkpoint inhibitors in mouse models. Here, we report that IL-18-primed natural killer (NK) cells enhanced the antitumor effects of anti-PD-1 antibodies by mobilizing type 1 conventional dendritic cells (cDC1s) to tumor sites and promoting type 1 immune responses. IL-18-primed NK cells had a premature phenotype, and expressed chemokines involved in cDC1 mobilization. In a combination treatment with IL-18 and anti-PD-1 antibody, NK cell depletion inhibited cDC1 mobilization and abrogated the therapeutic effects. Additionally, adoptive transfer of IL-18-primed NK cells induced cDC1 mobilization and enhanced the therapeutic effects of anti-PD-1 antibodies. IL-18 also increased IL-12 mRNA expression in DCs and IL-12 blood levels, and IL-12 upregulated XCL1 expression in NK cells. These results suggest that IL-18 primes NK cells and enhances the therapeutic effects of immune checkpoint inhibitors by promoting a feed-forward loop involving DCs.