European Journal of Immunology最新文献

Fibroblastic reticular cells (FRCs) are pivotal stromal components that maintain the structure of secondary lymphoid tissues and modulate the immune responses within the lymphoid microenvironment. In response to specific immune or inflammatory stimuli, such as infection or autoimmune triggers, FRCs undergo significant metabolic reprogramming. This process, originally characterized in cancer research, involves the regulation of key metabolic enzymes, pathways, and metabolites, resulting in functional transformations of these cells. Specifically, viruses stimulate FRCs to enhance the tricarboxylic acid cycle, while rheumatoid arthritis and sepsis prompt FRCs to increase oxidative phosphorylation. These changes enable FRCs to adapt their functions, such as proliferation or cytokine secretion, thereby effectively regulating the immune microenvironment to meet the dynamic needs of the immune system. This review provides a comprehensive update on the metabolic reprogramming of FRCs, highlighting how these changes support immune tolerance and response under varied physiological conditions.

Autoantibodies against cytokines (c-aAb) have been implicated in the pathophysiology of autoimmune diseases, and a variety of infections. In addition, several independent studies have detected elevated titers of c-aAb in the circulation of healthy individuals. To further understand their impact on immune responses, we measured c-aAb against IFN-α, IFN-γ, CSF2, IL-1α, IL-6, and IL-10 in the plasma of 1000 healthy individuals of the Milieu Intérieur (MI) cohort. Focusing on donors above a defined positive cut-off we observed significant age effects for c-aAb against IL-1α, but no major environmental or lifestyle associated factors were identified. Using TruCulture stimulation data from the MI cohort, we observed a strong association between induced IL-1α and c-aAb levels after LPS stimulation. For several other stimuli, c-aAb against IL-1α and IL-10 were associated with decreased or increased proinflammatory gene expression, respectively. Finally, TruCulture assays supplemented with plasma containing high-titer c-aAb showed a strong influence of anti-IFN-α and anti-IL-6 c-aAb on both baseline and induced gene expression. In summary, this study shows a widespread prevalence of anti-cytokine autoantibodies in healthy donors with impacts on diverse immune responses, suggesting a significant contribution of c-aAb to interindividual immune heterogeneity.

Reconstitution of the thymus is essential for assessing thymic function following injury. However, the currently employed cytoreductive regimes unvaryingly affect the thymic microenvironment, thereby impeding the recovery of T lymphopoiesis. The thymic stroma is composed of epithelial and mesenchymal cells. Thymic mesenchymal cells originate from the Neural crest (NC) and mesoderm and contribute to thymus organogenesis, yet their role in thymic regeneration is unclear. In this study, using transgenic mice expressing NC-specific Cre and Cre-driven DT receptors, we investigated the role of NC-derived mesenchymal cells in thymic regeneration following total body irradiation. We revealed that NC-derived mesenchymal cells have reduced susceptibility to irradiation and induce the upregulation of hematopoietic factors that promote thymus regeneration after irradiation. Additionally, using adult thymic organ culture and renal capsule transplantation, depletion of NC-derived mesenchymal cells resulted in a reduction of DN1-like early T-cell progenitors (ETP) and impaired thymic regeneration. Furthermore, among the numerous factors upregulated by NC-derived mesenchymal cells, Periostin and Flt3L were markedly increased after irradiation and promoted abundance of DN1-like ETPs during thymic reconstitution. Collectively, these findings highlight the importance of NC-derived mesenchymal cells in thymic regeneration.

Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome caused by inborn errors of cytotoxicity. Patients with biallelic PRF1 null mutations (encoding perforin) usually develop excessive immune cell activation, hypercytokinemia, and life-threatening immunopathology in the first 6 months of life, often without an apparent infectious trigger. In contrast, perforin-deficient (PKO) mice only develop HLH after systemic infection with lymphocytic choriomeningitis virus (LCMV). We hypothesized that restricted microbe-immune cell interactions due to specific pathogen-free (SPF) housing might explain the need for this specific viral trigger in PKO mice. To investigate the influence of a "wild" microbiome in PKO mice, we fostered PKO newborns with Wildling microbiota ('PKO-Wildlings') and monitored them for signs of HLH. PKO-Wildlings survived long-term without spontaneous disease. Also, systemic infection with vaccinia virus did not reach the threshold of immune activation required to trigger HLH in PKO-Wildlings. Interestingly, after infection with LCMV, PKO-Wildlings developed an altered HLH pattern. This included lower IFN-γ serum levels along with improved IFN-γ-driven anemia, but more elevated levels of IL-17 and increased liver inflammation compared with PKO-SPF mice. Thus, wild microbiota alone is not sufficient to trigger HLH in PKO mice, but host-microbe interactions shape inflammatory cytokine patterns, thereby influencing manifestations of HLH immunopathology.

Background: Head and neck squamous cell carcinoma (HNSCC) is linked to human papillomavirus (HPV) infection. HPV-positive and HPV-negative HNSCC exhibit distinct molecular and clinical characteristics. Although checkpoint inhibitors have shown efficiency in recurrent/metastatic HNSCC, response variability persists regardless of HPV status. This study aimed to explore the CD8⁺ T-cell landscape in HPV-negative HNSCC.

Methods: We performed simultaneous single-cell RNA and TCR sequencing of CD8⁺ tumor-infiltrating lymphocytes (TILs) from treatment-naïve HPV-negative HNSCC patients. Additionally, cells were stimulated ex vivo, which allowed for the tracking of clonal transcriptomic responses.

Results: Our analysis identified a subset of CD8⁺ TILs highly enriched for interferon-stimulated genes (ISG). TCR analysis revealed ISG cells are clonally related to a population of granzyme K (GZMK)-expressing cells. However, unlike GZMK cells, which exhibited rapid effector-like phenotypes following stimulation, ISG cells were transcriptionally inert. Additionally, ISG cells showed specific enrichment within tumor and were found across multiple tumor entities.

Conclusions: ISG-enriched CD8⁺ TILs are a consistent feature of various tumor entities. These cells are poorly understood but possess characteristics that may impact antitumor immunity. Understanding the unique properties and functionality of ISG cells could offer innovative treatment approaches to improve patient outcomes in HPV-negative HNSCC and other cancer types.

B cells differentiate from hematopoietic stem cells in the bone marrow (BM) and migrate as transitional cells to the spleen where final maturation takes place. Due to the enormous diversity in variable (V) regions of B cell receptors for antigen (BCR), B cells with complementary BCRs are likely to be generated. These could encounter each other in the BM or in secondary lymphoid organs. The outcome of such an event is unknown. To study this issue, we used two strains of gene-modified mice whose B cells display complementary BCRs. B cells of one strain express an idiotype⁺ (Id⁺) BCR while B cells of the other strain display an anti-idiotypic (αId) BCR. In vitro, B cells with complementary BCRs killed each other in a mechanism that required physical binding between BCR V-regions. In contrast, killing was unilateral in vivo: αId B cells with a follicular (FO) B cell phenotype were expanded, while Id⁺ B cells with a marginal zone (MZ) phenotype became deleted. The results show that B cells with complementary BCRs can recognize and regulate each other in vivo. This mechanism should be taken into account in theories for idiotypic regulation of the immune system.

• Aging leads to chronic inflammation and immune dysfunction, heightening the risk of myeloid malignancies like MDS and CMML. • Both aging and MDS show alterations in monocyte subtypes and function. Aging boosts inflammatory genes upregulation, whereas MDS favors antigen presentation, reflecting distinct immune and disease-specific adaptations. • MDS shows reduced inflammatory activity in CD14⁺ cells, whereas CMML exhibits heightened inflammation, highlighting distinct disease mechanisms.

The use of immunosuppressive treatment is required to prevent rejection events, even a long time after kidney transplantation despite rare recipients achieving long-term graft stability without the need for immunosuppressive treatment, called operationally tolerant patients (TOLs). We comprehensively investigate the immune system of long-term IS recipients (LTTs) and TOLs to highlight their shared and unique immune features. Blood immune cell phenotyping was performed by spectral cytometry. Samples from 34 individuals were analyzed, including 6 LTTs, 8 TOLs, 10 stable patients at 1 year posttransplantation (STAs), and 10 healthy volunteers. B cells differed between LTTs and TOLs with a decreased total B-cell frequency and the acquisition of a memory phenotype in LTTs whereas a naive phenotype is maintained in TOLs. The frequencies of IgD^-CD27^- B cells and CD11c⁺ memory B cells are increased in LTTs, with an exhausted phenotype, evoked by a significant decrease in CD25 expression. These CD11c⁺ B cells display an exhausted phenotype similar to those found in several chronic immune diseases in which they have been shown to participate in their pathophysiology, suggesting active chronic inflammation in LTTs. Altogether, these data indicate that precautions should be taken to minimize IS use.

In systemic lupus erythematosus (SLE), neutrophil dysregulation and neutrophil extracellular traps (NETs) formation contribute to disease pathogenesis, potentially worsening the autoimmune response. Although research indicates NETs' involvement in various autoimmune conditions, their relationship with regulatory T cells (Tregs) in SLE remains elusive. In this study, in vivo experiments were involved in administering NET injections to C57BL/6 and MRL/Ipr mice. In vitro, a co-culture system facilitated interaction between Tregs and NETs. Proteomic analysis elucidated NET composition, while RNA sequencing delineated their impact on Treg differentiation. We demonstrated that increased NET levels correlate inversely with Treg abundance in SLE patients, influencing both their proportion and functionality. NET administration reduced Treg levels and induced lupus-like symptoms in C57BL/6 mice, exacerbating symptoms in MRL/Ipr mice. DNase I treatment mitigated NET effects, restoring Treg levels and alleviating symptoms. RNA sequencing revealed altered gene expression in naïve CD4⁺ T cells exposed to NETs. Additionally, proteomic analysis showed S100A10 protein changes between SLE patients and healthy controls, hindering Treg differentiation. NETs influence TLR-4 of naïve CD4⁺ T cells via S100A10, thereby modulating Treg proportion and functionality. These findings highlight the critical role of NETs in Treg differentiation in SLE, suggesting that targeting NETs may provide a novel therapeutic approach.