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cROSs-presentation in pDCs: An energetic (m)CAT and mouse game

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Science Immunology  06 Jul 2018:
Vol. 3, Issue 25, eaau2829
DOI: 10.1126/sciimmunol.aau2829

Abstract

pDC cross-presentation of antigens to CD8+ T cells depends on mitochondrial generation of reactive oxygen species.

Optimal immune responses against viruses and tumors require effective CD8+ T cell priming through major histocompatibility complex class I (MHC-I) molecules, including cross-presentation of exogenous antigens by dendritic cells (DCs). Although conventional DCs (cDCs) cross-present antigen in steady state, plasmacytoid DCs (pDCs) appear to require Toll-like receptor (TLR) stimulation to effectively cross-present exogenous antigens to CD8+ T cells. Multiple mechanisms have been posited for TLR–mediated up-regulation of antigen cross-presentation in pDCs, but the specific intracellular pathways have been elusive. Understanding these mechanisms could pave the way for the development of effective therapeutics.

A NOX1/2 dependent pathway for Class I–mediated cross-presentation regulated by reactive oxygen species (ROS) production has been defined in cDCs and pDCs. Oberkampf and colleagues report a novel NOX1/2-independent pathway that allows pDCs to cross-present exogenous antigens to CD8+ T cells. NOX-dependent ROS inhibitors were able to inhibit cross-presentation in both cDCs and pDCs, However, after TLR stimulation in the absence of NOX1/2, only pDCs were able to cross-present exogenous antigens. Via genomic approaches in NOX1/2 knockout mice, the authors identified potential NOX1/2-independent target genes during TLR-induced pDC activation. Gene profiling suggested significant down-regulation of peroxide-degrading enzymes including catalase, a known inhibitor of mitochondrial ROS production. Using mCAT mice that transgenically express human catalase in their mitochondria, the authors showed that pDCs, which unlike cDCs increase mitochondrial respiration after activation, exhibited diminished cross-presentation of ovalbumin antigen and diminished CD8+ T cell activation in presence of excess catalase. These findings suggest that inhibition of the ROS-metabolizing enzyme catalase in mitochondria may be leveraged to increase ROS concentrations and cross-presentation in pDCs after TLR stimulation.

These findings highlight an important role for the energy machinery of innate immune cells (pDCs) in inducing effective adaptive immunity and suggest one metabolic mechanism by which innate activation of pDCs and cDCs may differ fundamentally. Enhancing mitochondrial ROS after TLR activation in pDCs may prove a valuable therapeutic target for improving antigen cross-presentation, adaptive immune responses, and vaccine efficacy.

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