Innate NLRC4 signaling controls adaptive immune responses

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Project Summary NLRC4 is a member of the Nucleotide-Binding Domain and Leucine-Rich Repeat Receptor (NLR) family of cytosolic pattern recognition receptors and is primarily expressed in innate immune cells. The canonical NLRC4 pathway is activated following the recognition of components of Gram-negative bacteria by NAIP proteins resulting in NLRC4 oligomerization and assembly of the inflammasome complex. Activation of the NLRC4 inflammasome culminates in caspase-1-mediated processing and release of the pro-inflammatory cytokine IL- 1. We have found that NLRC4 plays a protective role in mice challenged subcutaneously with either B16F10 melanoma cells or in a model of influenza A virus infection. In both models, Nlrc4-deficient (Nlrc4-/-) mice had a loss of effector CD4+ T cells. Generation and maintenance of robust T cell responses relies on T cell interactions with antigen presenting cells. Evaluation of Nlrc4-/- macrophages and dendritic cells (DC) revealed a downregulation of AKT1 and FoxO3a phosphorylation, which in turn resulted in the upregulation of the apoptosis- inducing ligand FasL on Nlrc4-/- myeloid cells that triggered cell death in co-cultured T cells. Importantly, unlike the canonical NLRC4 pathway, the anti-tumor and anti-viral roles of NLRC4 were inflammasome-independent, suggesting a novel non-canonical NLRC4 signaling pathway. In this proposal we will expand on these novel findings and utilize innovate technologies to probe unanswered questions. We hypothesize that endogenous danger signals activate NLRC4 in myeloid cell, which in turn maintains effector T cell responses by preventing FasL upregulation. We will define the mechanism by which NLRC4 is activated in antigen presenting cells and the novel non-canonical pathway through which NLRC4 modifies subsequent T cell responses. We will also determine what factors downregulate NLRC4 expression and how this downregulation can be exploited by pathogens and tumors. These studies will identify novel pathways in innate immune cells that can be targeted to either augment specific anti-tumor or anti-viral responses or inhibit pathogenic T cell responses.