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 Sh2d1a , which encodes SLAM-associated protein (SAP), a critical regulator of B:T synapses. We found that Mef2d regulates Sh2d1a 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 Il21 gene. In contrast, CD4 T cell–specific disruption of Mef2d led to a substantial increase in GC-T FH differentiation in response to protein immunization, concurrent with enhanced SAP expression. MEF2D 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.

SAP expressing T peripheral helper cells identify systemic lupus erythematosus patients with lupus nephritis

“…MEF2D mRNA expression inversely correlates with TFH populations, autoantibodies, and SLEDAI scores in SLE. 24 Our finding that SAP levels are increased in the circulation of SLE T cells, predominantly TFH and TPH cells, further supports the immunopathogenic role of SLAM-SAP signaling in SLE.…”

SAP-expressing T peripheral helper cells identify systemic lupus erythematosus patients with lupus nephritis

“…Similarly, repression of SAP gene transcription by a transcription factor myocyte enhancer factor 2 (Mef2d) has been shown to inhibit SAP-dependent T-B synapse formation and prevent antigen-specific CD4 T cells from differentiation into germinal center TFH cells. MEF2D mRNA expression inversely correlates with TFH populations, autoantibodies, and SLEDAI scores in SLE ( 26 ). Our finding that SAP levels are increased in the circulation of SLE T cells, predominantly TFH and TPH cells, further supports the immunopathogenic role of SLAM-SAP signaling in SLE.…”

Cytokines in Follicular Helper T Cell Biology in Physiologic and Pathologic Conditions

“…Our recent studies have shown that Mef2d functions as a transcriptional repressor of the Il21 gene, influencing IL-21 production through DNA binding. Mef2d binds to potential Mef2d binding sites in the Il21 gene, demonstrated by luciferase assays, and introducing Mef2d into CD4 T cells from naive mice markedly decreases IL-21 production ( 46 ). Overall, the regulation of IL-21 production in Tfh cells involves a complex network of TFs responding to various extracellular signals.…”