Project description:Single-cell RNA sequencing in seven anti-Ri autoimmune encephalitis (AIE) patients and three controls showed that neuron-reactive CD8+ T cells are cytotoxic KIR+ CD8+ regulatory T cells. In Ri-AIE, these cells had reduced KIR and IKZF2 (Helios) expression, alongside activated TCR signaling and elevated TNF and IFNG. They also overexpressed TOX, linked to brain-infiltrating cytotoxicity. These findings suggest a loss of regulatory function in KIR+ CD8+ T cells contributes to Ri-AIE pathogenesis.
Project description:We developed a B-cell-mediated mouse model of Anti-N-Methyl-D-aspartate receptor autoimmune encephalitis (AE) by immunization with a GluN1359–378 peptide. In our model, mice display a series of symptoms that recapitulate autoimmune encephalitis such as anxiety behaviour and spatial memory impairment (Wagnon et al, Brain 2020) . Proteomic analysis of AE meninges showed enrichment of differentially expressed proteins in biological processes associated with B cell activation and cytokine signalling pathways.
Project description:In 2022, a global mpox outbreak occurred, and remains a concern today. The T cell memory response to MPXV infection has not been fully investigated. In this study, we evaluated this response in convalescent and MVA-BN vaccinated individuals using VACV-infected cells. Detailed phenotypic and scRNAseq analysis was focused on the immunodominant HLA-A*02:01-G5R18-26-specific CD8+ T cell response. T cells from convalescent individuals showed greater cytotoxicity, migratory potential to site of infection and TCR clonal expansion. Our study suggests a better functional profile of MPXV-specific memory T cells induced by natural infection, which may have an implication on the long-term protective responses to future infection.
Project description:Autoimmune inflammation results from dysregulated immune responses, in which dysfunction of regulatory T cells (Tregs) is recognized as a key contributing factor due to their essential role in maintaining immune homeostasis and preventing autoimmunity. The stability and functionality of Tregs are heavily influenced by their immune microenvironment, including inflammatory and tumor contexts. Tregs comprise diverse subsets, but the distinctions and interactions among these populations remain poorly understood. Although CD8+ T cells have been implicated in autoimmune disease pathogenesis, their interactions with CD4+ Foxp3+ Tregs and the underlying regulatory mechanisms are not well characterized. In this study, we identified CD8+ T cells as crucial enhancers of CD4+ induced Treg (iTreg) differentiation, function, and stability. CD8+ T cells markedly upregulated the expression of CD39, Helios, CTLA-4, and CD103 in iTregs, enhancing their immunosuppressive capacity. In a naive CD4+ T cell transfer colitis model, co-transfer of naive CD8+ T cells ameliorated colitis by boosting iTreg-mediated suppression of Th1 and Th17 responses. Mechanistically, we found that CD8+ T cells regulate iTreg phenotypes through a ROS/TGF-beta signaling axis, with IRF4 in CD8+ T cells playing a central role. Furthermore, CD8+ T cell-primed iTregs exhibited superior therapeutic efficacy in an autoimmune arthritis model by suppressing Th1/Th17 responses and preserving endogenous Treg populations. These findings reveal a novel role for CD8+ T cells in supporting iTreg-mediated immune regulation and suggest a promising approach for enhancing Treg-based therapies in autoimmune diseases.
Project description:Primary biliary cholangitis (PBC) is a cholestatic autoimmune liver disease secondary to an autoreactive T cell response against intrahepatic small bile ducts. Multiple murine models have demonstrated the critical role of effector CD8+T cells in this response and our work has used IL-12p40-/-IL-2Rα-/- mice (DKO mice) to study this issue. Herein we first demonstrated that use of either a CD8a knock-out or an anti-CD8a antibody prevents/reduces biliary immunopathology. Bulk and single-cell RNA sequencing analysis identifies CD8+ tissue resident memory T cells (Trm) in the liver of DKO mice, which highly express activation and cytotoxicity associated markers and have the ability to induce apoptosis of bile duct epithelial cells. Liver CD8+Trm cells also upregulate expression of several immune checkpoint molecules and in particular we identified PD-1 as a specific liver CD8+Trm cell marker in this model. Based on these data we constructed a novel chimeric antigen receptor containing a PD-L1 extracellular domain to target PD-1-expressing CD8+Trm cells. Importantly, treatment of DKO mice with PD-1 targeting CAR-T cells selectively depleted liver CD8+Trm cells in vivo and alleviated autoimmune cholangitis.