Connexin-43: More than just a gap junction protein. Connexin-43 controls CD4+T cell activation and clonal expansion

Abstract Activation and proliferation of antigen specific T cells depends on the interaction of multiple signaling molecules with the TCR/CD3 complex. We report that expression of connexin 43 (Cx43), a gap junction protein, is critical for the expansion of antigen-specific or self-reactive effector CD4 +T cells. While gap junction mediated intercellular communication has been the main focus of connexin research, the cytoplasmic C-terminus of Cx43 has multiple functions independent of membrane channel forming properties and may act as a docking molecule for assembling signaling complexes including the immunological synapse. We also report that antigen-specific Cx43-deficient CD4 +T cells transferred into recipient mice immunized with cognate antigenic peptide and adjuvant expanded poorly compared to wild type cells. This protected mice from experimental autoimmune encephalomyelitis (EAE). Decreased proliferation and expansion also protects lymphopenic mice repopulated with naive, Cx43 deficient CD4 +T cells, from inflammatory bowel disease. We have found that Cx43-deficient CD4 +T cells have a signaling defect affecting Erk, p38 and Akt signaling pathways. Transcriptome RNA-seq analysis comparing gene expression profiles of activated Cx43 sufficient and deficient CD4 +T cells shows that differentially expressed genes are enriched in genes involved in G protein and Ca 2+signaling, ATP metabolism, genes regulating cytoskeleton reorganization and T cell homing. In summary, our data demonstrate that Cx43 has a major impact on the generation of effector CD4 +T cells, their ability to respond to antigenic stimulation, or to precipitate autoimmune disease.