Poster Sessions

APO -6

Andrew Snow

A. L. Snow, R. A. Marsh, P. Roehrs, L. R. Young, J. van Hoff, K. Zhang, A. H. Filipovich, H. C. Su, J. J. Bleesing, M. J. Lenardo

SAP is essential for TCR-induced apoptosis – a fresh perspective on X-linked lymphoproliferative disease.

Proper regulation of the immune response requires elimination of activated T lymphocytes via programmed cell death (apoptosis) to prevent unintended tissue damage and potential autoimmunity. One way that activated T cells are instructed to die occurs upon high-dose antigen restimulation through the T cell receptor (TCR), which sets a threshold for controlled T cell expansion. The significance of this “propriocidal” apoptosis pathway was originally appreciated in patients with autoimmune lymphoproliferative syndrome (ALPS), in which debilitating mutations in Fas, a key molecule implicated in TCR-induced death, result in profound lymphocyte accumulation, autoimmune manifestations, and increased incidence of lymphoma development. X-linked lymphoproliferative disease (XLP) is a rare primary immunodeficiency caused by mutations in the gene encoding signaling lymphocyte activation molecule (SLAM)-associated protein (SAP). Although XLP is frequently associated with fulminant Epstein Barr virus (EBV)-associated infectious mononucleosis, clinical manifestations reminiscent of ALPS (T cell hyperactivity, lymphoproliferative disease) also occur in the absence of EBV. We recently studied four SAP-deficient, EBV-naïve XLP patients who developed lymphoproliferative disease. Immunologic evaluation of these patients revealed signs of hyperactive T cell responses correlated with previous infections. Strikingly, activated XLP patient T cells were specifically resistant to death induced by T cell receptor (TCR) restimulation. Knockdown of SAP expression in normal donor cells using RNA interference recapitulated this defect in both CD4+ and CD8+ T cells without altering naive T cell activation, suggesting SAP is critical for a specific TCR-induced apoptotic signal in effector cells. In fact, upregulation of key apoptosis effector molecules (e.g. Fas ligand, BIM) following restimulation was impaired in SAP-deficient cells, suggesting that loss of SAP dampens pro-apoptotic signals originating from the TCR signaling complex. Collectively, our data suggests that defective T cell homeostasis, associated with resistance to TCR-induced apoptosis, contributes to lymphoproliferative disease in XLP patients. These results offer new insight into how EBV, which resides in antigen-presenting B cells, may induce the unbridled expansion of SAP-deficient T cells through repeated restimulation, resulting in the devastating disease that most XLP patients ultimately succumb to.