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. The Journal of Immunology, 2011, 187: 248-257.