Details

Autor(en) / Beteiligte

• Kuczma, Michal
• Wang, Cong-Yi
• Ignatowicz, Leszek
• Gourdie, Robert
• Kraj, Piotr

Titel

Altered connexin 43 expression underlies age dependent decrease of Treg cell suppressor function in NOD mice

Ist Teil von

• The Journal of immunology (1950), 2015-04, Vol.194 (11), p.5261-5271

Erscheinungsjahr

2015

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Type I diabetes (T1D) is one of the most extensively studied autoimmune diseases but the cellular and molecular mechanisms leading to T cell-mediated destruction of insulin-producing β-cells are still not well understood. Here we show that T reg cells in NOD mice undergo age-dependent loss of suppressor functions exacerbated by the decreased ability of activated effector T cells to upregulate Foxp3 and generate T reg cells in the peripheral organs. This age-dependent loss is associated with reduced intercellular communication mediated by gap junctions, which is caused by impaired upregulation and decreased expression of connexin 43. Regulatory functions can be corrected, even in T cells isolated from aged, diabetic mice, by a synergistic activity of retinoic acid, TGF-β, and IL-2, which enhance connexin 43 and Foxp3 expression in T reg cells and restore the ability of conventional CD4 + T cells to upregulate Foxp3 and generate peripherally derived T reg cells. Moreover, we demonstrate that suppression mediated by T reg cells from diabetic mice is enhanced by a novel reagent, which facilitates gap junction aggregation. In summary, our report identifies gap junction-mediated intercellular communication as an important component of the T reg cell suppression mechanism compromised in NOD mice and suggests how T reg mediated immune regulation can be improved.