Autosomal Dominant Hyper-IgE Syndrome Patients Retain IL10-Producing preTh17-Cells That Are Activated by Opportunistic Pathogens and Support IgE Production Giorgia Moschetti, Chiara Vasco, Francesca Clemente, Paola Larghi, Sara Maioli, et al. Allergy European Journal of Allergy and Clinical Immunology, 2026 Background Autosomal Dominant‐Hyper‐IgE Syndrome (AD‐HIES) is caused by dominant‐negative (DN) STAT3 mutations and characterized by high IgE levels, a lack of Th17‐cells, and recurrent infections with extracellular pathogens. We previously identified an enigmatic population of IL‐10 producing CCR6 + B‐helper T‐cells and investigated here their relationship to Th17‐cells and STAT3 signaling requirements. Methods Human blood lymphocytes were analyzed by multiparametric flow cytometry in healthy donors and AD‐HIES patients. Analysis was performed by conventional gating or with bioinformatic tools. FACS‐purified T‐cell subsets were activated in vitro and Th17 differentiation assessed. T‐cell antigen specificities were assessed by activation with heat‐killed pathogens or antigenic peptide pools. B helper capacities were determined according to antibody secretion in B‐T co‐cultures by ELISA. Results CCR6 + Th‐cells that lacked subset‐defining differentiation markers (“CCR6 SP ”) were mostly non‐polarized central memory T‐cells (T CM ) that produced IL‐10 and expressed RORγt. They were pre‐committed to a Th17 fate, since TCR stimulation in the absence of polarizing cytokines induced efficient Th17 differentiation. The latter was promoted by an autocrine loop of STAT3‐activating cytokines. CCR6 + Th‐cells were reduced in patients with DN‐STAT3 mutations but contained activated CCR6 SP T‐cells that produced IL‐10 and responded vigorously to AD‐HIES‐associated pathogens. These residual CCR6 + Th‐cells provided B‐cell help for IgG and IgE production. Conclusions Th17 differentiation in AD‐HIES patients was not completely impaired but arrested at an intermediate stage of IL‐10‐producing “pre‐Th17”‐cells. Surprisingly, DN‐STAT3 mutations did not inhibit IL‐10 production by CD4 + T‐cells. Pre‐Th17‐cells were activated by AD‐HIES‐associated pathogens and possessed B‐helper functions, suggesting that they are not protective but may promote aberrant IgE production.
V-ATPase in glioma stem cells: a novel metabolic vulnerability Alessandra Maria Storaci, Irene Bertolini, Cristina Martelli, Giorgia De Turris, Nadia Mansour, et al. Journal of Experimental and Clinical Cancer Research, 2025 Background Glioblastoma (GBM) is a lethal brain tumor characterized by the glioma stem cell (GSC) niche. The V-ATPase proton pump has been described as a crucial factor in sustaining GSC viability and tumorigenicity. Here we studied how patients-derived GSCs rely on V-ATPase activity to sustain mitochondrial bioenergetics and cell growth. Methods V-ATPase activity in GSC cultures was modulated using Bafilomycin A1 (BafA1) and cell viability and metabolic traits were analyzed using live assays. The GBM patients-derived orthotopic xenografts were used as in vivo models of disease. Cell extracts, proximity-ligation assay and advanced microscopy was used to analyze subcellular presence of proteins. A metabolomic screening was performed using Biocrates p180 kit, whereas transcriptomic analysis was performed using Nanostring panels. Results Perturbation of V-ATPase activity reduces GSC growth in vitro and in vivo. In GSC there is a pool of V-ATPase that localize in mitochondria. At the functional level, V-ATPase inhibition in GSC induces ROS production, mitochondrial damage, while hindering mitochondrial oxidative phosphorylation and reducing protein synthesis. This metabolic rewiring is accompanied by a higher glycolytic rate and intracellular lactate accumulation, which is not exploited by GSCs for biosynthetic or survival purposes. Conclusions V-ATPase activity in GSC is critical for mitochondrial metabolism and cell growth. Targeting V-ATPase activity may be a novel potential vulnerability for glioblastoma treatment.
The Human Bone Marrow May Offer an IL-15-Dependent Survival Niche for EOMES+ Tr1-Like Cells Nadia Pulvirenti, Chiara Vasco, Camilla Righetti, Petra Dadova, Giacomo Boffa, et al. European Journal of Immunology, 2025 Maintenance of memory T‐cells in the bone marrow and systemically depends on the homeostatic cytokines IL‐7 and IL‐15. An immunological memory may also exist for regulatory T‐cells. EOMES+type‐1 regulatory (Tr1)‐like cells have a rapid in vivo turnover, but whether they are short‐lived effector cells or are maintained long‐term has not been investigated.EOMES+Tr1‐like cells expressing GzmK were enriched among CD69+Ki67−T‐cells in the bone marrow of healthy donors, suggesting that they became quiescent and bone marrow‐resident. Conversely, CD4+GzmB+ effector T‐cells were excluded from the bone marrow‐resident fraction. The dichotomy between GzmK+ and GzmB+T‐cells was observed both in healthy individuals and in multiple sclerosis patients, and also among CD8+T‐cells. Intriguingly, bone marrow‐resident CD4+ memory T‐cells expressed increased levels of IL‐7Rα, while EOMES+Tr1‐like cells were consistently IL‐7Rαlo. However, EOMES+Tr1‐like cells expressed the IL‐2/15Rβ chain, and the latter was induced upon forced expression of EOMES in primary human CD4+ T‐cells. Finally, IL‐15 rescued EOMES+Tr1‐enriched populations from death by neglect but was not required for CD4+ memory T‐cell survival. These findings suggest that the bone marrow may provide a survival niche for EOMES+Tr1‐like cells. The different IL‐7 and IL‐15 receptor expression patterns of CD4+ memory T‐cells and EOMES+Tr1‐like cells suggest furthermore that they compete for different homeostatic niches.
Reduced spike specific T-cell responses in COVID-19 vaccinated subjects undergoing SARS-CoV-2 breakthrough infection Stefania Varchetta, Federica Sole Golfetto, Patrizia Bono, Annapaola Callegaro, Tanya Fabbris, et al. Frontiers in Immunology, 2025 IntroductionT-cell responses to SARS-CoV-2 remain largely preserved across variants despite waning neutralizing antibodies. However, T-cell immunity may vary with the host’s immune status, and data on T-cell responses in post-vaccine infections (PVI) are limited.MethodsWe assessed Spike-specific T-cell responses in 32 vaccinated individuals, 16 of whom experienced PVI. Immune responses were evaluated at three time points: 1 month after the second vaccine dose (T1), 1 month after the booster dose (T2), and, in the PVI group, 1–3 months after the first positive nasal swab (T3). Additionally, we evaluated anti-spike antibody levels, T-cell exhaustion markers, and natural killer cell subsets, focusing on memory-like CD57+ NKG2C+ cells.ResultsSubjects who developed PVI exhibited significantly reduced Spike-specific CD4 T-cell responses following the booster dose compared to vaccinated individuals who remained uninfected. This was accompanied by increased frequencies of LAG-3+ CD4+ and CD8+ T-cells. A positive correlation was observed between AIM+ CD4+ T-cells and NKG2C+ NK cells at T2 in PVI subjects. Following natural infection, T-cell responses were enhanced and associated with an expansion of NKG2C+ NK cells.ConclusionsIndividuals experiencing PVI displayed impaired booster-induced CD4+ T-cell responses and increased expression of the immune checkpoint LAG-3. Natural infection restored and enhanced cellular immunity, particularly through the expansion of Spike-specific T-cells and memory NK cell populations. This study identifies an immune profile characterized by low spike-specific responses, which are associated with an increased susceptibility to breakthrough infections.
CD4+ T Cells from Healthy Subjects and Colon Cancer Patients Recognize a Carcinoembryonic Antigen-specific Immunodominant Epitope Cancer Research, 2003
