Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in patients with autoimmune diseases 9193

Abstract Description Autoreactive CD4+ cells control the immune response in chronic autoimmune diseases but remain difficult to track. The ex vivo characterization of autoreactive T cells is essential to understand their function and how they adapt to chronic autoimmunity. Neuromyelitis optica spectrum disorder is a prototypic autoimmune disease of the central nervous system targeting aquaporin-4 (AQP4). AQP4-specific CD4+ T cells are centrally involved in disease development. However, their functional and molecular properties are poorly characterized. We combined HLA-tetramer- and antigen-reactive T cell enrichment and scRNA sequencing to characterize ex vivo AQP4-specific CD4+ T cells isolated from blood of patients and healthy donors. Surprisingly, in AQP4-antibody+ NMOSD patients, autoreactive T cells showed reduced proliferative capacity and pro-inflammatory cytokines. Instead, exhaustion-associated co-inhibitory receptors were co-expressed together with FOXP3. The proliferative blockade of autoreactive T cells was reversed in vitro by checkpoint inhibition. The same exhaustion-like phenotype was demonstrated in autoimmune hepatitis and bullous pemphigoid. We identified a new exhaustion-like T cell phenotype and a potential role of FOXP3 for the regulation of chronic autoreactivity in human autoimmune disease. Our data suggest CD4+ T cell exhaustion as a common mechanism of adaptation to chronic self-stimulation across disease types with important implications for their therapeutic targeting Topic Categories Basic Autoimmunity (BA)