Response to Comment on: Meagher et al. Neutralization of Interleukin-16 Protects Nonobese Diabetic Mice From Autoimmune Type 1 Diabetes by a CCL4-Dependent Mechanism. Diabetes 2010;59:2862–2871

We thank Vendrame and Dotta (1) for their interesting perspective regarding our recently published study investigating the role of interleukin-16 (IL-16) in the development of insulitis and type 1 diabetes in female NOD mice (2). On the basis of previous studies correlating suboptimal activation of caspase-3 with the development of autoimmunity in the clinical setting (3,4), they propose a similar condition might exist in NOD mice, resulting in defective secretion of mature IL-16. Although we have not directly examined this possibility, it must be considered that many studies have wrestled with the difficulty in detecting secreted IL-16 in several mouse strains used to examine inflammatory responses (2,5). This likely reflects the biology of mature IL-16, which is active at concentrations as low as 10⁻¹¹ M, and indicates that the low levels of intrapancreatic mature IL-16 detected during the development of insulitis is not restricted only to the NOD genetic background.

However, the notion that caspase-3 activation may be suboptimal in NOD mice is suggested by several articles reporting that T cells in NOD mice exhibit an altered signaling cascade downstream of the T-cell receptor, resulting in a hyporesponsive state of activation and resistance to activation-induced cell death (6–8). Importantly, although it may be that a reduction in caspase-3 activation leads to diminished IL-16 secretion, this correlation has not yet been proven and the level of activated caspase-3 required for cleavage of pro–IL-16 is unknown. Thus, in support of the perspective by Vendrame and Dotta, it is uncertain how a partial deficiency in caspase-3 activation would affect levels of IL-16 secretion; but clearly, based on our results, the level of caspase-3 activation occurring in lymphocytes is sufficient for the secretion of IL-16 and recruitment of T cells needed for disease pathology. Collectively, a partial deficiency in caspase-3 activation may contribute to T-cell resistance to activation-induced cell death, which would enable autoreactive T cells to persist and may also facilitate their recruitment to islets via secretion of mature IL-16.