The transcription factor Mef2d regulates B:T synapse–dependent GC-T _FH differentiation and IL-21–mediated humoral immunity

Abstract

Communication between CD4 T cells and cognate B cells is key for the former to fully mature into germinal center-T follicular helper (GC-T_FH) cells and for the latter to mount a CD4 T cell-dependent humoral immune response. Although this interaction occurs in a B:T synapse-dependent manner, how CD4 T cells transcriptionally regulate B:T synapse formation remains largely unknown. Here, we report that Mef2d, an isoform of the myocyte enhancer factor 2 (Mef2) transcription factor family, is a critical regulator of this process. In CD4 T cells, Mef2d negatively regulates expression of <i>Sh2d1a</i>, which encodes SLAM-associated protein (SAP), a critical regulator of B:T synapses. We found that Mef2d regulates <i>Sh2d1a</i> expression via DNA binding-dependent transcriptional repression, inhibiting SAP-dependent B:T synapse formation and preventing antigen-specific CD4 T cells from differentiating into GC-T_FH cells. Mef2d also impeded IL-21 production by CD4 T cells, an important B cell help signaling molecule, via direct repression of the <i>Il21</i> gene. In contrast, CD4 T cell-specific disruption of <i>Mef2d</i> led to a substantial increase in GC-T_FH differentiation in response to protein immunization, concurrent with enhanced SAP expression. <i>MEF2D</i> mRNA expression inversely correlates with human systemic lupus erythematosus (SLE) patient autoimmune parameters, including circulating T_FH-like cell frequencies, autoantibodies, and SLEDAI scores. These findings highlight Mef2d as a pivotal rheostat in CD4 T cells for controlling GC formation and antibody production by B cells.