Emerging evidence indicates that innate immunodeficiency syndromes are linked to mutations in innate receptors and to specific infections. X-linked lymphoproliferative syndrome type-2 (XLP-2) is associated with deficiency in X-linked inhibitor of apoptosis protein (XIAP), with poorly understood molecular mechanisms. Here we showed that XIAP-deficiency selectively impaired BCL10-mediated innate responses to dectin-1 ligands, but did not affect responses to various Toll-like receptor (TLR) agonists. Consequently, Xiap-/- mice became highly vulnerable upon Candida albicans infection. The compromised early innate responses led to persistent presence of C. albicans and inflammatory cytokines in Xiap-/- mice. Furthermore, priming of Xiap-/- mice with dectin-1 ligand curdlan alone resulted in XLP-2-like syndromes. Restoration of dectin-1-induced Rac1 activation and phagocytosis by resolvin D1, but not up-regulation of NF-kappaB, rescued Xiap-/- mice from C. albicans lethal infection. Therefore, development of XLP-2 in XIAP-deficient patients could be partly due to sustained inflammation as a consequence of defective BCL10-dependent innate immunity toward specific pathogens. Importantly, our results suggest the potential therapeutic value of resolvin D1 in the treatment of XLP-2 and innate immunodeficiency syndromes.
