NLRP10 is a NOD-like receptor essential to initiate adaptive immunity by dendritic cells

Abstract

NLRs (nucleotide-binding domain leucine-rich repeat containing receptors; NOD-like receptors) are a class of pattern recognition receptor (PRR) that respond to host perturbation from either infectious agents or cellular stress1,2. The function of most NLR family members has not been characterized and their role in instructing adaptive immune responses remains unclear 2,3. NLRP10 (also known as PYNOD, NALP10, PAN5 and NOD8) is the only NLR lacking the putative ligand binding leucine rich repeat domain, and has been postulated to be a negative regulator of other NLR members including NLRP34–6. We did not find evidence that NLRP10 functions through an inflammasome to regulate caspase-1 activity nor that it regulates other inflammasomes. Instead, Nlrp10−/− mice had a profound defect in helper T cell-driven immune responses to a diverse array of adjuvants including lipopolysaccharide (LPS), aluminium hydroxide (alum) and complete Freund’s adjuvant (CFA). Adaptive immunity was impaired in the absence of NLRP10 due to a dendritic cell (DC) intrinsic defect in emigration from inflamed tissues while upregulation of DC costimulatory molecules and chemotaxis to CCR7-dependent and independent ligands remained intact. The loss of antigen transport to the draining LN by this migratory DC subset resulted in an almost absolute loss in naïve CD4+ T cell priming, highlighting the critical link between diverse innate immune stimulation, NLRP10 activity and the immune function of mature DCs.