European Journal of Immunology最新文献

Spondylarthritides (SpA) are a group of autoinflammatory diseases affecting the spine, peripheral joints, and entheses, including axial spondyloarthritis (axSpA) and psoriatic arthritis. AxSpA has a multifactorial etiology that involves genetic predispositions, such as HLA-B27 and IL-23R. Although HLA-B27 is strongly associated with axSpA, its role remains unclear. GWAS studies have demonstrated that genetic polymorphisms related to the IL-23 pathway occur throughout the spectrum of SpA, including but not limited to axSpA and PsA. IL-23 promotes the production of IL-17, which drives inflammation and tissue damage. This pathway contributes not only to peripheral enthesitis but also to spinal inflammation. γδ T cells in axSpA express IL-23R and RORγt, crucial for their activation, although specific pathogenic cells and factors remain elusive. Despite drug efficacy in PsA, IL-23R inhibition is ineffective in axSpA. Murine models provide valuable insights into the intricate cellular and molecular interactions that contribute to the development and progression of SpA. Those models are useful tools to elucidate the dynamics of γδ T cell involvement, offering insights into disease mechanisms and potential therapeutic targets. This review aims to illuminate the complex interplay between IL-23 and γδ T cells in SpA pathogenesis, emphasizing their roles in chronic inflammation, tissue damage, and disease heterogeneity.

Sepsis affects 25 million children per year globally, leading to 2.9 million deaths and substantial disability in survivors. Extensive characterization of interactions between the host and bacteria in children is required to design novel preventive and therapeutic strategies tailored to this age group. Vγ9Vδ2 T cells are the first T cells generated in humans. These cells are defined by the expression of Vγ9Vδ2 T-cell receptors (TCRs, using the TRGV9 and TRDV2 gene segments), which react strongly against the prototypical bacterial phosphoantigen HMBPP. We investigated this reactivity by analyzing the TCR δ (TRD) repertoire in the blood of 76 children (0–16 years) with blood culture-proven bacterial sepsis caused by HMBPP-positive Escherichia coli or by HMBPP-negative Staphylococcus aureus or by HMBPP-negative Streptococcus pneumoniae. Strikingly, we found that S. aureus, and to a lesser extent E. coli but not S. pneumoniae, shaped the TRDV2 repertoire in young children (<2 years) but not in older children or adults. This dichotomy was due to the selective expansion of a fetal TRDV2 repertoire. Thus, young children possess fetal-derived Vγ9Vδ2 T cells that are highly responsive toward specific bacterial pathogens.

Acinetobacter baumannii is an opportunistic Gram-negative bacterium representing one of the leading causes of ventilator-associated pneumonia. The development of pneumonia results from a complex interplay between pathogens and pulmonary innate mucosal immunity. Therefore, the knowledge of the host immune responses is pivotal for the development of effective therapeutics to treat A. baumannii infections. Previous studies were conducted using cell lines and animal models, but a comprehensive understanding of the interaction between A. baumannii and primary human immune cells is still lacking. To bridge this gap, we investigated the response of primary monocytes, macrophages, and dendritic cells to the A. baumannii-type strain and an epidemic clinical isolate. We found that all immune cells trigger different responses when interacting with A. baumannii. In particular, macrophages and monocytes mediate bacterial clearance, whereas monocytes and dendritic cells activate a late response through the production of cytokines, chemokines, and the expression of co-stimulatory molecules. The epidemic strain induces lower expression of interleukin-10 and CD80 compared with the type strain, potentially constituting two immune evasion strategies.

Although the functions of tyrosine phosphatases in T-cell biology have been extensively studied, our knowledge on the contribution of serine/threonine phosphatases in T cells remains poor. Protein phosphatase 2A (PP2A) is one of the most abundantly expressed serine/threonine phosphatases. It is important in thymocyte development and CD4⁺ T-cell differentiation. Utilizing a genetic model in which its catalytic subunit alpha isoform (PP2A Cα) is deleted in T cells, we investigated its contribution to CD8⁺ T-cell homeostasis and effector functions. Our results demonstrate that T-cell intrinsic PP2A Cα is critically required for CD8⁺ T-cell homeostasis in secondary lymphoid organs and intestinal mucosal site. Importantly, PP2A Cα–deficient CD8⁺ T cells exhibit reduced proliferation and survival. CD8⁺ T-cell antibacterial response is strictly dependent on PP2A Cα. Expression of Bcl2 transgene rescues CD8⁺ T-cell homeostasis in spleens, but not in intestinal mucosal site, nor does it restore defective antibacterial responses. Finally, proteomics and phosphoproteomics analyses reveal potential targets dependent on PP2A Cα, including mTORC1 and AKT. Thus, PP2A Cα is a key modulator of CD8⁺ T-cell homeostasis and effector functions.

Cigarette smoke (CS) is a major risk factor for chronic lung diseases and promotes activation of pattern recognition receptors in the bronchial epithelium. NOD-like receptor family, pyrin domain-containing 3 (NLRP3) is a pattern recognition receptor whose activation leads to caspase-1 cleavage, maturation/release of IL-1β and IL-18, and eventually pyroptosis. Whether the NLRP3 inflammasome participates in CS-induced inflammation in bronchial epithelial cells is still unclear. Herein, we evaluated the involvement of NLRP3 in CS-induced inflammatory responses in human primary bronchial epithelial cells. To this purpose, human primary bronchial epithelial cells were stimulated with CS extracts (CSE) and lytic cell death, caspase activation (-1, -8, -3/7), cytokine release (IL-1β, IL-18, and IL-8), NLRP3, pro-IL-1β/pro-IL-18 mRNA, and protein expression were measured. The impact of inhibitors of NLRP3 (MCC950), caspases, and the effect of the antioxidant N-acetyl cysteine were evaluated. We found that CSE increased pro-IL-1β expression and induced activation of caspase-1 and release of IL-1β and IL-18. These events were independent of NLRP3 and we found that NLRP3 was not expressed. N-acetyl cysteine reverted CSE-induced caspase-1 activation. Overall, our findings support that the bronchial epithelium may play a central role in the release of IL-1 family cytokines independently of NLRP3 in the lungs of smokers.

The migration is the key step for thymic T cells to enter circulation and then lymph nodes (LNs), essential for future immune surveillance. Although promoter-based transcriptional regulation through Foxo1, Klf2, Ccr7, and Sell regulates T-cell migration, it remains largely unexplored whether and how enhancers are involved in this process. Here we found that the conditional deletion of Med1, a component of the mediator complex and a mediator between enhancers and RNA polymerase II, caused a reduction of both CD4⁺ and CD8⁺ T cells in LNs, as well as a decrease of CD8⁺ T cells in the spleen. Importantly, Med1 deletion hindered the migration of thymic αβT cells into the circulation and then into LNs, accompanied by the downregulation of KLF2, CCR7, and CD62L. Mechanistically, Med1 promotes Klf2 transcription by facilitating Foxo1 binding to the Klf2 enhancer. Furthermore, forced expression of Klf2 rescued Ccr7 and Sell expression, as well as αβT-cell migration into LNs. Collectively, our study unveils a crucial role for Med1 in regulating the enhancer-based Foxo1-Klf2 transcriptional program and the migration of αβT cells into LNs, providing valuable insights into the molecular mechanisms underlying T-cell migration.

In developing B cells, V(D)J gene recombination is initiated by the RAG1/2 endonuclease complex, introducing double-stranded DNA breaks (DSBs) in V, D, and J genes and resulting in the formation of the hypervariable parts of immunoglobulins (Ig). Persistent or aberrant RAG1/2 targeting is a potential threat to genome integrity. While RAG1 and RAG2 have been shown to bind various regions genome-wide, the in vivo off-target DNA damage instigated by RAG1/2 endonuclease remains less well understood. In the current study, we identified regions containing RAG1/2-induced DNA breaks in mouse pre-B cells on a genome-wide scale using a global DNA DSB detection strategy. We detected 1489 putative RAG1/2-dependent DSBs, most of which were located outside the Ig loci. DNA sequence motif analysis showed a specific enrichment of RAG1/2-induced DNA DSBs at GA- and CA-repeats and GC-rich motifs. These findings provide further insights into RAG1/2 off-target activity. The ability of RAG1/2 to introduce DSBs on the non-Ig loci during the endogenous V(D)J recombination emphasizes its genotoxic potential in developing lymphocytes.

Efficient identification of human monoclonal antibodies targeting specific antigenic sites is pivotal for advancing vaccines and immunotherapies against infectious diseases and cancer. Existing screening techniques, however, limit our ability to discover monoclonal antibodies with desired specificity. In this study, we introduce a novel method, blocking of binding (BoB) enzyme-linked immunoassay (ELISA), enabling the detection of high-avidity human antibodies directed to defined epitopes. Leveraging BoB-ELISA, we analyzed the antibody response to known epitopes of influenza A hemagglutinin (HA) in the serum of vaccinated donors. Our findings revealed that serum antibodies targeting head epitopes were immunodominant, whereas antibodies against the stem epitope, although subdominant, were highly prevalent. Extending our analysis across multiple HA strains, we examined the cross-reactive antibody response targeting the stem epitope. Importantly, employing BoB-ELISA we identified donors harboring potent heterosubtypic antibodies targeting the HA stem. B-cell clonal analysis of these donors revealed three novel, genealogically independent monoclonal antibodies with broad cross-reactivity to multiple HAs. In summary, we demonstrated that BoB-ELISA is a sensitive technique for measuring B-cell epitope immunogenicity, enabling the identification of novel monoclonal antibodies with implications for enhanced vaccine development and immunotherapies.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with multifaceted pathogenetic processes, including abnormalities of T-cell subset distribution and function. Accumulation of senescent CD4⁺ T cells has been found to contribute to the development of the disease. In this issue, Jiang et al. provide compelling evidence that links an expanded pool of CD4⁺CD57⁺ senescent T cells in patients with SLE to disease activity favored by interleukin-15. Importantly, treatment of lupus-prone mice with a senolytic drug resulted in decreased autoimmune pathology. The findings of this study suggest possible novel therapeutics to treat patients with SLE.

Langerhans cells (LCs) are the key antigen-presenting cells in the epidermis in normal conditions and respond differentially to environmental and/or endogenous stimuli, exerting either proinflammatory or anti-inflammatory effects. Current knowledge about LCs mainly originates from studies utilizing mouse models, whereas with the development of single-cell techniques, there has been significant progress for human LCs, which has updated our understanding of the phenotype, ontogeny, differentiation regulation, and function of LCs. In this review, we delineated the progress of human LCs and summarized LCs’ function in inflammatory skin diseases, providing new ideas for precise regulation of LC function in the prevention and treatment of skin diseases.