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

One-Sentence Summary:

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. Though multiple mechanisms have been posited for TLR-mediated upregulation of antigen cross-presentation in pDCs, the specific intracellular pathways have been elusive. Understanding these mechanisms could pave the way for the development of effective therapeutics. In this article, Oberkampf and colleagues propose a novel and specific intracellular pathway for TLR-associated enhancement of cross-presentation by pDCs.

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. Here, the authors report a novel NOX1/2-independent pathway which 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 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 downregulation of peroxide-degrading enzymes including catalase, a known inhibitor of mitochondrial ROS production. Using mCAT mice, which 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 OVA antigen and diminished CD8+ T cell activation in presence of excess catalase. These finding suggest that inhibition of the ROS-metabolizing enzyme catalase in mitochondria may be leveraged to increase ROS concentrations and cross-presentation in pDCs following 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 following TLR activation in pDCs may prove a valuable therapeutic target for improving antigen cross-presentation, adaptive immune responses, and vaccine efficacy.