AIMp1 Potentiates TH1 Polarization and Is Critical for Effective Antitumor and Antiviral Immunity.

Dan Liang,Xiang Zhang,David B Corry,William K Decker,Shixia Huang,Doyeun Kim,Brian E Gilbert,Jonathan M Levitt,Farrah Kheradmand,Lin Tian,Vanaja Konduri,Sunghoon Kim,Yunyu C Baig,Ran You,Matthew M Halpert,Fuli Jia,Silke Paust

doi:10.3389/fimmu.2017.01801

Abstract

Dendritic cells (DCs) must integrate a broad array of environmental cues to exact control over downstream immune responses including TH polarization. The multienzyme aminoacyl-tRNA synthetase complex component AIMp1/p43 responds to cellular stress and exerts pro-inflammatory functions; however, a role for DC-expressed AIMp1 in TH polarization has not previously been shown. Here, we demonstrate that the absence of AIMp1 in bone marrow-derived DC (BMDC) significantly impairs cytokine and costimulatory molecule expression, p38 MAPK signaling, and TH1 polarization of cocultured T-cells while significantly dysregulating immune-related gene expression. These deficits resulted in significantly compromised BMDC vaccine-mediated protection against melanoma. AIMp1 within the host was also critical for innate and adaptive antiviral immunity against influenza virus infection in vivo. Cancer patients with AIMp1 expression levels in the highest tertiles exhibited a 70% survival advantage at 15-year postdiagnosis as determined by bioinformatics analysis of nearly 9,000 primary human tumor samples in The Cancer Genome Atlas database. These data establish the importance of AIMp1 for the effective governance of antitumor and antiviral immune responses.

Highlights

Of the professional antigen-presenting cell (APC) subsets, dendritic cells (DCs) are the most specialized and efficient in the priming of de novo T-cell responses and serve as a critical bridge between innate and adaptive immunity
Antitumor immunity is broadly dependent upon T helper 1 (TH1) immune processes for destruction of neoplastic cells [34,35,36], and immunity to B16 melanoma is known to be dependent upon TH1 T-cell generation [37]
The trend was well reflected by Kaplan–Meier survival analysis (Figure 1D). These results indicated that bone marrow-derived DC (BMDC)-expressed AIMp1 is critical for vaccine-mediated rejection of immunogenic melanoma tumor, whereas the impact of AIMp1 in host effector cells appeared to have little relevance in this regard

Summary

Introduction

Of the professional antigen-presenting cell (APC) subsets, dendritic cells (DCs) are the most specialized and efficient in the priming of de novo T-cell responses and serve as a critical bridge between innate and adaptive immunity In this sentinel capacity, DC must detect, process, and integrate a broad array of environmental cues to generate downstream responses best-tailored to specific pathogenicities. T-helper type 1 (TH1) polarization is associated with the generation of cell-mediated adaptive responses provided by effector cells including CD4+ T helper 1 (TH1) cells and CD8+ cytotoxic T lymphocytes (CTLs) and is characterized by the secretion of IL-12 and IFN-γ from APC and T-cells, respectively [4] These types of adaptive responses are known to be critical for effective clearance of intracellular infection and well correlated with positive outcomes in cancer [5,6,7]. Interrogation of the critical factors that govern the TH1 immune response enhance the effort to manipulate adaptive immunity for medical benefit [13, 14]

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Results

Conclusion