Abstract The inability to generate effective cell-mediated immunity outside the context of live virus vaccination continues to be a pervasive clinical problem for vaccination of immunocompromised individuals, cell-mediated prophylaxis of viral diseases for which no live vaccines exist, and critically, the generation of durable antitumor immune responses. Cell mediated immunity is initiated by dendritic cells (DC), a critical lineage of innate immunity that serves as the principal point of contact and crosstalk between the innate and adaptive arms of the immune system. Successful response to pathogen requires that DC detect and integrate a broad array of environmental cues to exact control over critical downstream responses, particularly T-helper (TH) cell polarization. Many such cues, as well as mechanisms of detection and integration, remain to be understood. In this proposal we will interrogate the emerging but well-supported hypothesis that DC expression of the novel regulator AIMp1 drives physiologic propagation of TH1 cellular immunity. This hypothesis is based upon extensive and rigorous data demonstrating that genetic ablation of AIMp1 produces deficits in TH1 polarization significantly more profound than those characterized in IL-12 or IL-12R-deficient mice. AIMp1 knockout mice lose the ability to mount an adaptive immune response against influenza, exhibiting complete lethality to a normally sublethal challenge, deficient HA-specific IgG2a production, and loss of nearly all IFN-g-secreting T-cells in the lung by post-infection day 15. AIMp1-/- animals also exhibited complete loss of antitumor immunity that could be rescued by adoptive transfer of wildtype DC. Mechanistically, the data suggest these deficits are due to defective p38MAPK activation in AIMp1-/- DC with downstream dysregulation of AP-1 heterodimerization. Direct relevance of AIMp1 to human disease was validated through a pan-cancer TCGA bioinformatics analysis of 9,000 primary human tumor sam- ples, revealing an unexpected 70% survival advantage among patients expressing elevated levels of AIMp1 in the primary tumor. In this dataset, elevated AIMp1 expression was highly correlated with an activated DC gene signature and TH1 immune profile. Strikingly, this survival advantage was not recapitulated among patients in which the primary tumor exhibited high levels of IL-12A (p35) expression. These data suggest an unrecognized yet indispensable role for DC-expressed AIMp1 in adaptive TH1 governance and provide a cogent rationale for this study: confirmation that a novel regulatory factor is essential for integration and transduction of TH1-inducing signals in DC will alter the paradigm by which TH1 immune signaling is presently understood. The mechanisms through which AIMp1 governs cellular immunity will be determined by the completion of three specific aims. In aim I we will define the in vivo DC subset(s) for which AIMp1 function is critical to propagation of TH1 immunity. In ai...