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摘要： The cGAS-STING pathway mediates the innate immune response to cytosolic DNA, contributing to surveillance against microbial invasion or cellular damage. Once activated, STING recruits TBK1 at the trans-Golgi network (TGN), which in turn phosphorylates IRF3 to induce type I interferon (IFN-I) expression. In contrast to STING, little is known about how TBK1 is transported to the TGN for activation. Here, we show that multiple TGN tethering factors, a group of proteins involved in vesicle capturing, are indispensable for STING-IFN-I signaling. Deletion of TBC1D23, a recently reported tethering factor, in mice impairs the STING-IFN-I signaling, but with insignificant effect on STING-NF-kappa B signaling. Mechanistically, TBC1D23 interacts with TBK1 via the WASH complex subunit FAM21 and promotes its endosome-to-TGN translocation. Furthermore, multiple TGN tethering factors were reduced in aged mice and senescent fibroblasts. In summary, our study uncovers that TGN tethering factors are key regulators of the STING-IFN-I signaling and suggests that their reduction in senescence may produce aberrant STING signaling.

关键词： SARS-CoV-2   Omicron   cellular immune response   CD8 T-cell epitope   conserved epitope  

摘要： Introduction Recent surveillance has identified the emergence of the SARS-CoV-2 Omicron ariant, which exhibits the ability to evade multiple neutralizing antibodies generated by prior infection or vaccination. However, significant knowledge gaps remain regarding the CD8 T-cell immune reactivity to the Omicron variant. This study aims to evaluate the characteristics of HLA-A2-restricted CD8 T-cell epitopes from the Omicron variant and analyze epitope-specific CD8 T-cell responses to SARS-CoV-2 inactivated vaccines. Methods We conducted a comprehensive analysis of CD8 T-cell responses to SARS-CoV-2 inactivated vaccines, focusing on HLA-A2-restricted epitopes derived from the Omicron variant. Mutant epitopes were evaluated for their impact on antigen presentation and CD8 T-cell immune reactivity. Additionally, we screened for epitopes that exhibited reduced CD8 T-cell responses following the emergence of the Omicron variant. Results Our findings revealed that mutant epitopes in the Omicron variant led to escape from antigen presentation and diminished CD8 T-cell immune responses. We identified two epitopes associated with decreased CD8 T-cell reactivity post-Omicron variant emergence. Notably, we discovered an S protein epitope, 67A>V, which demonstrated similar proportions of CD8 T-cell specificity between the ancestral and mutant strains, suggesting its conservation and potential immunogenicity for vaccine development. Furthermore, the third dose of the inactivated vaccine significantly increased the number of epitope-specific CD8 T cells, underscoring the importance of booster doses in enhancing cellular immune responses against the Omicron variant. Discussion This study highlights the ability of the Omicron variant to evade CD8 T-cell immune responses through epitope mutations, while also identifying conserved epitopes with potential utility in vaccine design. The observed increase in epitope-specific CD8 T cells following a booster dose emphasizes the critical rol

关键词： hypomorphic variants   IL2RG gene   common cytokine receptor gamma chain   flow cytometry standardization   STAT3 and STAT5 phosphorylation   T and B cell proliferation   plasmablast differentiation   NK degranulation  

摘要： Background Over the last decade, the identification of hypomorphic variants in patients previously diagnosed with Common Variable Immunodeficiency (CVID) has led to the association of milder phenotypes with variants of the IL2RG gene that are usually related to severe combined immunodeficiency. Indeed, several revertant mosaicisms have been described in cases with hypomorphic variants in that gene. Our main objective herein was the functional characterization of p. (Pro58Thr) variant in the IL2RG gene in an adult patient with antibody deficiency and moderate CD4+ T cell *** Evaluation of the patient included a clinical examination and a complete analysis of the peripheral blood phenotype. To further explore IL2RG functionality we selected downstream signaling readouts, namely STAT3 and STAT5 phosphorylation, NK degranulation and B- and T-cell proliferation capacity in vitro, which can be measured by flow cytometry, that reflect the strength of homeostatic signaling pathways in resting cells and after *** The patient presented reduced CD132 expression and conserved T- and B-cell proliferation capacity in vitro. However, we found that intracellular signaling downstream of IL2 gamma c is affected, with reduced STAT3 phosphorylation after IL-21 stimulation in B cells and CD4 T cells. In addition, CD4+ T cells showed a reduced STAT5 phosphorylation in response to IL-2, which was not so evident in CD8+ T cells. NK degranulation was impaired upon PHA and IL-2 as well as plasmablast differentiation in *** We conclude that p. (Pro58Thr) in the IL2RG gene is functionally a hypomorphic variant, as reported previously. Although the functionality of CD8+ is less impaired than the rest of the lymphocyte subsets, we did not detect a reversion of the variant in isolated CD8+, CD4+, CD19+ or NK cells.

关键词： anti-TNF alpha   pancreas transplantation   allograft thrombosis   allograft rejection   ischemia/reperfusion   inflammation  

摘要： The rate of early pancreas allograft failure remains high due to thrombosis but also to severity of rejection episodes. We investigated if adjunct anti-TNF alpha therapy was safe and could improve outcomes after pancreas transplantation. We investigated all pancreas transplants performed in our institution between 2010 and 2022. Etanercept, an anti TNF alpha therapy, was added to our standard immunosuppressive regimen since 2017 after approval from our institutional human ethics committee. Pancreas survival, rejection episodes, as well as infectious complications were analyzed. A total of 236 pancreas transplants were included, among whom 87 received Etanercept for induction. In multivariable analysis, after adjustment on confounding variables, pancreas survival did not differ between groups (HR = 0.92, CI 95% = 0.48;1.73, p = 0.79). However, patients receiving Etanercept presented a significantly lower occurrence of pancreas rejection in multivariate analysis (HR = 0.36, CI 95% = 0.14;0.95, p = 0.04). Patients receiving Etanercept did not experienced a higher risk of bacterial, fungal, CMV nor BK virus infections compared to the non-treated group. The use of anti-TNF alpha after pancreas transplantation was safe and did not increase infectious complications. Despite a similar rate of thrombosis, anti-TNF alpha significantly reduced pancreatic rejection, thus supporting its use among pancreas transplant recipients.

关键词： Interleukin-2 (IL-2)   Interleukin-2 receptor (IL-2R)   T cell growth factor   Regulatory T cells (Tregs)   autoimmunity   cancerimmunology   transplantation  

摘要： BackgroundThe discovery of interleukin-2 (IL-2) and its receptor (IL-2R) almost 50 years ago revolutionized immunology, marking a pivotal moment in understanding T cell biology and immune regulation. Initially identified as a T cell growth factor, IL-2 unveiled critical insights into cytokine-mediated immune cell proliferation and *** review highlighted the characterization of IL-2R as a multi-chain receptor complex set a precedent for decoding cytokine receptor signaling. The unique interplay between IL-2 and its high-affinity receptor component, IL-2R alpha, epitomizes the principle of specificity and efficiency in cytokine signaling, enabling precise immune modulation. Regulatory T cells (Tregs) exploit IL-2R alpha high affinity to outcompete effector T cells for IL-2, ensuring immune tolerance and preventing *** its foundational role in immune homeostasis, leveraging IL-2 for therapeutic purposes has proven ***-2-based therapies hold transformative potential in autoimmunity, cancer immunology, and transplantation, yet they remain elusive due to the complex balance between immunostimulatory and immunosuppressive effects. This review explores the milestones in IL-2 biology, its dualistic functions, and the ongoing quest to harness its therapeutic promise.

关键词： TPL2   Tpl2 kinase   NLRP3 inflammasome   interferons   type I IFN   IL-1b  

摘要： The NLRP3 inflammasome complex is an important mechanism for regulating the release of pro-inflammatory cytokines, IL-1 beta and IL-18, in response to harmful pathogens. Overproduction of pro-inflammatory cytokines has been linked to cryopyrin-associated periodic syndrome, arthritis, and other inflammatory conditions. It has been previously shown that tumor progression locus 2, a serine-threonine kinase, promotes IL-1 beta synthesis in response to LPS stimulation;however, whether TPL2 kinase activity is required during inflammasome priming to promote Il1b mRNA transcription and/or during inflammasome activation for IL-1 beta secretion remained unknown. In addition, whether elevated type I interferons, a consequence of either Tpl2 genetic ablation or inhibition of TPL2 kinase activity, decreases IL-1 beta expression or inflammasome function has not been explored. Using LPS-stimulated primary murine bone marrow-derived macrophages, we determined that TPL2 kinase activity is required for transcription of Il1b, but not Nlrp3, Il18, caspase-1 (Casp1), or gasdermin-D (Gsdmd) during inflammasome priming. Both Casp1 and Gsdmd mRNA synthesis decreased in the absence of type I interferon signaling, evidence of crosstalk between type I interferons and the inflammasome. Our results demonstrate that TPL2 kinase activity is differentially required for the expression of inflammasome precursor cytokines and components but is dispensable for inflammasome activation. These data provide the foundation for the further exploration of TPL2 kinase inhibitor as a potential therapeutic in inflammatory diseases.

关键词： immunoproteasome   IL-4RA   type 2 inflammation   precision-cut lung slices   airway hyperresponsiveness  

摘要： Introduction Immunoproteasome (IP) is induced by pro-inflammatory stimuli such as interferon gamma to regulate inflammation and immunity. Asthma patients with airway type 2 high inflammation (e.g., IL-13) demonstrate more eosinophils and airway hyperresponsiveness (AHR) with less interferon gamma. The role of IP in regulating airway eosinophilic inflammation and AHR has not been *** This study was aimed to determine how IP regulates type 2 inflammation and AHR using LMP7 (a subunit of IP) deficient mouse lungs, precision-cut lung slices (PCLS), and cultured human airway epithelial cells treated with IL-13 in the absence or presence of an IP inhibitor ONX-0914 or exogenous *** LMP7 KO mouse lungs had significantly more IL-4R alpha protein expression than the wildtype (WT) mice. Following IL-13 treatment in PCLS, LMP7 KO mice had significantly more airway contraction than WT mice, which was coupled with increased eotaxin-2 levels. IP inhibition by ONX-0914 in IL-13 treated human airway epithelial cells resulted in significantly more IL-4R alpha protein expression and eotaxin-3 release. IP inhibition in human PCLS significantly increased *** Collectively, these data demonstrated that IP promotes degradation of IL-4R alpha, while inhibits type 2 inflammation and AHR. Enhancement of IP expression or activity may serve as an alternative approach to reduce the severity of type 2 inflammation and AHR.

关键词： SARS-CoV-2   T-cell immunity   humoral immunity   mRNA vaccines   cross-reactivity   hybrid immunity  

摘要： The contributions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells to vaccine efficacy and durability are unclear. We investigated relationships between mRNA vaccine-induced spike-specific interferon- gamma (IFN-gamma) and interleukin-2 (IL-2) T-cell responses and neutralizing antibody development in long-term care home staff doubly vaccinated with BNT162b2 or mRNA-1273. The impacts of pre-existing cross-reactive T-cell immunity on cellular and humoral responses to vaccination were additionally assessed. Mathematical modeling of the kinetics of spike-specific IFN-gamma and IL-2 T-cell responses over 6 months post-second dose was bifurcated into recipients who exhibited gradual increases with doubling times of 155 and 167 days or decreases with half-lives of 165 and 132 days, respectively. Differences in kinetics did not correlate with clinical phenotypes. Serological anti-spike IgG, anti-receptor binding domain (RBD) IgG, anti-spike IgA, and anti-RBD IgA antibody levels otherwise decayed in all participants with half-lives of 63, 57, 79, and 46 days, respectively, alongside waning neutralizing capacity (t(1/2) = 408 days). Spike-specific T-cell responses induced at 2-6 weeks positively correlated with live viral neutralization at 6 months post-second dose, especially in hybrid immune individuals. Participants with pre-existing cross-reactive T-cell immunity to SARS-CoV-2 exhibited greater spike-specific T-cell responses, reduced anti-RBD IgA antibody levels, and a trending increase in neutralization at 2-6 weeks post-second dose. Non-spike-specific T-cells predominantly targeted SARS-CoV-2 non-structural protein at 6 months post-second dose in cross-reactive participants. mRNA vaccination was lastly shown to induce off-target T-cell responses against unrelated antigens. In summary, vaccine-induced spike-specific T-cell immunity appeared to influence serological neutralizing capacity, with only a modest effect induced by pre-existing c

关键词： 结核分枝杆菌(Mtb)   耻垢分枝杆菌(Ms)   脯氨酸-脯氨酸-谷氨酸-59(PPE59)   Rv3429   生物学功能   免疫应答  

摘要： 目的 研究结核分枝杆菌（Mtb）脯氨酸-脯氨酸-谷氨酸-59（PPE59）对耻垢分枝杆菌（Ms）生物学功能及调控宿主细胞免疫应答的影响。方法 通过PCR扩增获得PPE59基因片段，将其克隆至pALACE，构建重组pALACE-PPE59载体，电转化至Ms；采用Western blot法对PPE59表达进行鉴定和亚细胞定位分析。分析Ms＿Vec和Ms＿PPE59在低酸（pH=3和pH=5）条件和表面活性压力十二烷基硫酸钠（SDS）条件的存活能力，以及其在巨噬细胞内存活率。ELISA检测Ms＿Vec和Ms＿PPE59感染巨噬细胞后，白细胞介素1β（IL-1β）、IL-6、IL-12和肿瘤坏死因子α（TNF-α）、IL-10分泌水平。结果 PPE59蛋白定位于Ms细胞壁，可增强Ms的耐酸作用和抗SDS作用，有利于Ms在巨噬细胞内的存活；PPE59显著降低促炎细胞因子IL-1β、IL-6、IL-12和TNF-α的分泌，促进抑炎因子IL-10的分泌。结论 PPE59能增强Ms对低酸和SDS压力条件下的存活能力，通过调控细胞因子分泌水平促进其在细胞内的存活。

关键词： antigen presentation/processing   MHC class I   dendritic cells   cytotoxic T cells   Tapasin  

摘要： Endogenous and exogenous antigen processing and presentation through the MHC class I peptide-loading complex (PLC) are essential for initiating cytotoxic T lymphocyte responses against pathogens and tumors. Tapasin, a key component of the PLC, is produced in multiple isoforms through alternative splicing, each isoform influencing the assembly and stability of MHC class I molecules differently. While the canonical Tapasin isoform plays a critical role in stabilizing MHC class I by facilitating optimal peptide loading in the endoplasmic reticulum (ER), the other isoforms function in distinct ways that impact immune regulation. This study aimed to investigate the role of Tapasin isoforms, particularly soluble isoform 3, in modulating antigen presentation and immune responses, focusing on their effects on MHC class I peptide loading and surface expression. Our findings show that isoforms 1 and 2 stabilize TAP and facilitate efficient peptide loading onto MHC class I in the ER, promoting optimal antigen presentation. In contrast, isoform 3, which lacks both the ER retention signal and the transmembrane domain, is secreted and acts as a negative regulator. Isoform 3 inhibits the loading of exogenous peptides onto MHC class I molecules at the cell surface, thereby playing a critical role in the spatial and temporal regulation of MHC class I antigen presentation. The secreted Tapasin isoform 3 likely regulates immune responses by preventing inappropriate T cell activation and cytotoxicity, which could otherwise lead to immune-mediated tissue damage and contribute to autoimmune disorders. Understanding the distinct functions of Tapasin isoforms provides insights into immune regulation and highlights the importance of fine-tuning peptide-loading processes to ensure proper immune responses and prevent immune-related pathologies.