Pam3CSK4 enhanced beta cell loss and diabetogenesis: The roles of IFN-gamma and IL-17

Toll like receptors are primary sensors of both innate and adaptive immune systems. They activate APCs and influence T-cell function in inflammatory autoimmune response. Studies have shown that TLR manipulation may lead to either tolerance or trigger autoimmunity. Using diabetogenic and subdiabetogenic multiple low doses of streptozotocin, we demonstrate here that Pam3 CYS-CK4 a TLR-2 agonist, enhances and promotes diabetes in C57BL/6 male mice following increased apoptosis of 13 islet cells. FACS analysis of isolated pancreatic lymph node cells revealed significant increased number of macrophages, dendritic cells, CD4(+) CD4(+) TNF-alpha(+) IFN-gamma(+) and most significantly, CD4(+) IL-17(+) and reduced number of CD25(+) Fox T cells after Pam3CSK(4) treatment. Genetic deletion of prevents whereas deletion of IL-17 reduced severity of Pam3CSK(4)-induced enhancement of diabetes. TLR-2 agonist-enhanced diabetogenesis is also influenced by enhanced influx of antigen presenting cells and suppression of regulatory T cell activity. (C) 2013 Elsevier Inc. All rights reserved.