The development of spontaneous insulin-dependent diabetes mellitus is preceded by the organization of tertiary lymphoid organ (TLO) in situ, but its role in the development of tissue destruction and the cytokines that control such structures have not been fully defined. We have now observed that TNF superfamily 14 (TNFSF14) is upregulated in aged nonobese diabetic (NOD) pancreas with the appearance of TLO. Blockade of TNFSF14 signaling caused a substantial reduction in the expression of lymphotoxin β receptor (LTβR)-controlled migration factors within the islets and disrupts organization of tertiary structures, leading to prevention of diabetes. Consistently, enhancing LTβR signaling by transgenic expression of TNFSF14 in the islets of NOD mice rapidly promoted de novo formation of local TLO, resulting in diabetes, even in the absence of draining lymph nodes (LN). Thus, the TNFSF14-LTβR pathway appears to be critical in the development and maintenance of TLO for the onset of diabetes.
