CD4 ⁺ T _RM 17 cells become activated by inflammatory cytokines to produce IL-17A and thereby promote autoimmunity.

The P2X7 receptor is a ligand-gated, cation-selective channel whose main physiological ligand is ATP. P2X7 receptor activation may also be triggered by ARTC2.2-dependent ADP ribosylation in the presence of extracellular NAD. Upon activation, this receptor induces several responses, including the influx of calcium and sodium ions, phosphatidylserine externalization, the formation of a non-selective membrane pore, and ultimately cell death. P2X7 receptor activation depends on the availability of extracellular nucleotides, whose concentrations are regulated by the action of extracellular nucleotidases such as CD39 and CD38. The P2X7 receptor has been extensively studied in the context of the immune response, and it has been reported to be involved in inflammasome activation, cytokine production, and the migration of different innate immune cells in response to ATP. In adaptive immune responses, the P2X7 receptor has been linked to T cell activation, differentiation, and apoptosis induction. In this review, we will discuss the evidence of the role of the P2X7 receptor on T cell differentiation and in the control of T cell responses in inflammatory conditions.

γδ T cells are involved in the control of Staphylococcus aureus infection, but their importance in protection compared to other T cells is unclear. We used a mouse model of systemic S. aureus infection associated with high bacterial load and persistence in the kidney. Infection caused fulminant accumulation of γδ T cells in the kidney. Renal γδ T cells acquired tissue residency and were maintained in high numbers during chronic infection. At day 7, up to 50% of renal γδ T cells produced IL-17A in situ and a large fraction of renal γδ T cells remained IL-17A ⁺ during chronic infection. Controlled depletion revealed that γδ T cells restricted renal S. aureus replication in the acute infection and provided protection during chronic renal infection and upon reinfection. Our results demonstrate that kidney-resident γδ T cells are nonredundant in limiting local S. aureus growth during chronic infection and provide enhanced protection against reinfection.

Patients with autoimmune hepatitis (AIH) experience increased mortality and severe side effects from non-specific immunosuppressive therapy, highlighting an urgent need for targeted treatment approaches. Here, we aimed to delineate the cellular and molecular network underlying AIH within its spatial context and to validate a key therapeutic target in a clinical trial. We employed computational modelling, multi-omics analyses, and functional experiments to map the immune landscape of AIH. In addition, we conducted a steroid-free open-label phase IIa clinical trial using infliximab, a TNF-targeting antibody, in patients with AIH. Our studies revealed that myeloid cell and hepatocyte-derived IL-15 promotes cytotoxicity and proliferation of liver auto-aggressive CD8⁺ T cells. Full execution of their cytotoxic program is licensed by TNF derived from clonally expanded liver-resident CD4⁺ T cells. AIH hepatocytes respond to TNF by increasing expression of adhesion molecules, making them targets for both CD8⁺ and CD4⁺ T cells. In the clinical trial, targeting TNF with infliximab demonstrated efficacy as an entirely steroid-free AIH treatment. These findings elucidate the immune network in AIH and identify TNF as one of the central network nodes. Accordingly, our findings provide the basis for novel targeted, steroid-free immune therapies, including the use of infliximab. European Union Clinical Trials Register (EudraCT No.: 2017-003311-19). These findings have significant implications for the treatment of autoimmune hepatitis (AIH). By mapping the spatial and functional immune network within the AIH liver, this study identifies IL-15 and TNF as central drivers of T cell-mediated cytotoxicity, offering new precision targets for intervention. The successful use of infliximab as a steroid-free therapy in a phase II trial marks a pivotal step toward safer, more specific treatment options for patients with AIH. This research not only advances our understanding of AIH pathogenesis, but also sets the stage for broader application of immune-targeted therapies in autoimmune liver diseases.