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 (T _R) cells are poorly understood. We have found that connexin 43 (Cx43), expressed by thymic T_R cells progenitors, supports T _R development. Mice with deletion of the Cx43 gene induced in T cells produce only few T_R cells and had increased proportion of activated T cells in the lymph nodes, suggesting impaired peripheral tolerance. Reduction of the T_R 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 T_R cells. We propose that a possible mechanism of Cx43 activity is by regulating Foxp3 expression in T_R lineage cells.