LO-008 MEF2D (Mef2d) expression in CD4 T cells influences humoral autoimmunity by regulating follicular helper T cell differentiation and function

BackgroundSystemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by autoantibody production and follicular helper T cells (Tfh) play a crucial role in this process. A recent study revealed that a rare genetic variant in the myocytes enhancer factor 2D (MEF2D) gene is found in a subgroup of Swedish SLE patients and is strongly associated with autoantibodies. Considering that the MEF2D transcription factor is known to negative regulator in neuronal synapse formation, we hypothesized that MEF2D expression in CD4 T cells controls Tfh differentiation and humoral (auto)immunity by regulating B:T synapse formation.MethodsMEF2D expression was measured in total peripheral blood CD4 T cells of healthy individuals and SLE patients and was compared with the magnitude of autoimmune features. The function of Mef2d in Tfh differentiation and humoral immunity was investigated with murine antigen (Ag)-specific CD4 T cells in the context of protein immunization.ResultsCD4 T cells of SLE patients had significantly downregulated MEF2D expression compared to those of healthy individuals with robust negative associations with circulating Tfh (cTfh) cell frequency and autoimmune parameters of SLE. Ectopic Mef2d expression in murine Ag-specific CD4 T cells led to profound defects in germinal center (GC)-Tfh differentiation and GC formation after NP-OVA immunization by directly suppressing the Sh2d1a gene that encodes SAP. Consequently, Mef2d overexpressed CD4 T cells exhibited lower conjugate formation with cognate Ag-presenting B cells compared to those of control. Mef2d deficiency in CD4 T cells, on the contrary, resulted in a spark increase in GC-Tfh differentiation with enhanced SAP expression implying that Mef2d expression in CD4 T cells is associated with abnormal Tfh cell generation.ConclusionsThese data provide important implications for the regulatory function of MEF2D (Mef2d) in modulating (aberrant) Tfh differentiation and TD humoral (auto)immunity.