European Journal of Immunology最新文献

Cellular metabolism intricately directs the differentiation, stability, and function of regulatory T cells (Tregs), which are pivotal in immune regulation. Metabolic reprogramming enables Tregs to adapt to diverse tissue environments; however, it can also disturb immune equilibrium, driving their conversion into unfavorable states like exTregs that hinder regulation in autoimmunity and transplantation. Purine metabolism has emerged as a critical but underexplored regulator of Treg biology. Beyond their traditional roles in nucleotide synthesis and energy balance, purine metabolites also serve as potent second messengers shaping Treg phenotype, suppressive capacity, and adaptability in inflammatory, autoimmune, and transplant environments. Extracellular ATP promotes inflammation, while adenosine supports Treg-mediated immunosuppression, highlighting a dual and context-dependent nature of purinergic signaling. This review outlines current findings on intracellular and extracellular purine metabolism in Tregs, emphasizing key enzymes and purinergic receptors that sustain Treg phenotype and resilience. It discusses disruptions in purine signaling compromising Treg functions, identifies knowledge gaps, and proposes future research directions for potential therapeutic strategies in immune-related ailments.

Peripherally derived regulatory T cells (pTregs) have a prominent role in maintaining intestinal immune homeostasis. In cases of phosphoinositide-3-kinase δ (PI3Kδ) inactivation, such as in patients receiving PI3Kδ inhibitor idelalisib as a cancer treatment, breakdown of intestinal immune tolerance occurs frequently in the form of diarrhea and colon inflammation. In a mouse model of systemic PI3Kδ inactivation, both enhancement of antitumor immunity and colitis have been described as a result of Treg impairment. However, in view of the critical role for Tregs in the prevention of systemic autoimmunity, the basis for such tissue-restricted breach of immune tolerance upon loss of PI3Kδ function is not yet understood. We report here that mice lacking PI3Kδ activity do not suffer a general defect in Treg immunosuppression, but specifically fail to develop Helios⁻ pTregs in the colon. We demonstrate reduced extrathymic Treg induction, in vitro and in vivo, from naïve CD4⁺ T cells with inactive PI3Kδ, along with dysregulation of a tissue-resident phenotype. These results suggest a nonredundant role for PI3Kδ-dependent pTreg differentiation in maintaining tolerance to commensal microbial antigens in the gut.

Lymphoid follicles in the human gut are critical immune hubs, yet their role in Crohn's disease pathogenesis remains poorly understood. Here, we apply multiplexed imaging mass cytometry to spatially profile Peyer's patches and lymphoid follicles in biopsies from healthy controls and Crohn's disease patients with ileitis, isolated colonic involvement, or in remission. Despite tissue heterogeneity, our optimized preprocessing pipeline enabled robust tissue annotation, single-cell phenotyping, and neighbourhood-level analysis. While conventional analysis based on cell frequencies did not distinguish disease states, spatial analysis revealed disease-associated remodelling of lymphoid architecture. Biopsies from colonic Crohn's disease patients showed, within follicles, increased frequencies of activated CD8⁺ T cells and a reduction in naïve T cells, alongside enrichment of B cell–T cell interaction neighbourhoods. These alterations were most pronounced in smaller B-cell patches, suggesting more functionally dynamic immune-cell interactions in compact lymphoid structures. In contrast, Crohn's disease ileitis samples closely resembled healthy tissue, with minimal structural or immune cell perturbations. Our data support a model in which Peyer's patches and lymphoid follicles undergo structural and functional remodelling in response to colonic inflammation. These findings underscore the value of spatially resolved immune profiling to uncover tissue-specific immune dynamics in inflammatory bowel disease.

The cover image is based on the article Activation of CD8⁺ T cells in the human ex vivo lung tumor microenvironment using anti-CD3/CD28 and Nivolumab by Tonia Bargmann et al., https://doi.org/10.1002/eji.70060

Assessing chromatin accessibility in rare cell populations within tissue remains a key challenge. To address this, we present a low-input ATAC workflow optimized for liver ILCs. The protocol is validated across cell numbers, Tn5 ratios, and library preparation steps and unveils unique epigenetic features of liver NK cells and ILC1s.

TNF is a pleiotropic cytokine with immunomodulatory functions mediated by its interaction with the receptor TNFR2, highly expressed by Tregs. However, Tregs can also produce TNF, and an autocrine TNF-TNFR2 loop has been proposed. Here, we describe that both human and mouse Tregs produce TNF in physiological conditions, in several mouse organs, and in mouse models of chronic inflammation and cancer. However, TNF production and TNFR2 expression are differentially distributed: indeed, TNFR2⁺ and TNFR2⁻ Treg subsets are, respectively, poor and strong TNF producers. The two subsets of TNFR2⁺ and TNFR2⁻ Tregs partially maintain their different ability to produce TNF when separately stimulated ex vivo. However, when cocultured, the TNFR2⁺ cells greatly outnumber the TNFR2⁻ counterpart and induce in TNFR2⁻ cells the upregulation of Foxp3 and TNFR2, in association with the transfer of cytoplasmic material. Functionally, TNFR2⁺ Tregs display superior suppressive activity and survival in vitro, both related to an improved resistance to oxidative stress. Overall, our data indicate that Tregs exist in two states, respectively committed to TNF production or TNF sensing through TNFR2, which cooperate in promoting the suppressive function of the whole Treg pool.

γδ T cells are unconventional T cells that group into different subsets based on the usage of variable γδ T cell receptor (TCR) gene segments, body location, and functionality. γδ T cells that secrete the proinflammatory cytokine interleukin 17 (IL-17) predominantly express a Vγ4⁺ or Vγ6⁺ γδ TCR. The biology and the importance of the γδ TCR of IL-17-producing γδ T cells are not well understood. Here, we investigated the IL-17 production capability of γδ T cells in mice deficient for Vγ4⁺ and Vγ6⁺ γδ TCRs using flow cytometry, TCR-seq, and single-cell transcriptomics. Our data show that Vγ1 T cells only partially compensate for the loss of IL-17⁺ Vγ4 and Vγ6 T cell subsets in lymphoid and nonlymphoid tissues. They develop pre- and postnatally and were predominantly detectable in their physiological body habitats. Collectively, the data underscore the nonredundant roles of Vγ4⁺ and Vγ6⁺ subsets in IL-17-mediated immunity.

Pregnancy requires immune tolerance to a semi-allogeneic fetus, involving profound adaptations, particularly in the T helper (Th) cell response. The intestinal microbiome plays a crucial role in health, but its influence on immune adaptation to pregnancy remains unclear. Bacterial extracellular vesicles (BEVs), released by gut bacteria, can cross the intestinal barrier and modulate immune responses. In our study we investigated the effect of fecal EVs (fEVs) from pregnant women on Th cell composition in vitro. fEVs were purified from preserved stool samples, characterized, and their uptake by immune cells was analyzed. Using an in vitro T cell culture model, we examined Th cell phenotypes, intracellular cytokine expression, and proteomic changes after stimulation with fEVs from pregnant and non-pregnant women. We demonstrate that fEVs from preserved stool samples are rapidly taken up by T cells and modulate their phenotype. Stimulation with fEVs from pregnant women shifts Th cells toward a regulatory profile favorable for pregnancy, increasing Th2 cells while reducing Th17 cells compared to fEVs from non-pregnant controls. This study provides the first in vitro evidence that fecal-derived EVs influence immune adaptation to pregnancy and may offer a basis for microbiome-targeted strategies to prevent or treat immunological pregnancy complications.