Connexin 43 Signaling Enhances the Generation of Foxp3+ Regulatory T Cells

Despite their importance for the functioning of the immune system, thymic development and peripheral maintenance of Foxp3+ regulatory T (TR) cells are poorly understood. We have found that connexin 43 (Cx43), expressed by thymic TR cells progenitors, supports TR development. Mice with deletion of the Cx43 gene induced in T cells produce only few TR cells and had increased proportion of activated T cells in the lymph nodes, suggesting impaired peripheral tolerance. Reduction of the TR cell numbers was accompanied by increased presence of CD4+CD25+GITR+Foxp3− T cells, which did not produce inflammatory cytokines and lost suppressor function. These results strongly argue that we have discovered a novel signaling pathway, controlled by Cx43, that enhances the generation of TR cells. We propose that a possible mechanism of Cx43 activity is by regulating Foxp3 expression in TR lineage cells.