Acute intermittent porphyria studies with fibroblasts.

Abstract

Common <i>IRF5</i> genetic risk variants associated with multiple immune-mediated diseases are a major determinant of interindividual variability in pattern-recognition receptor (PRR)–induced cytokines in myeloid cells. However, how myeloid cell–intrinsic IRF5 regulates the multiple distinct checkpoints mediating T cell outcomes in vivo and IRF5-dependent mechanisms contributing to these distinct checkpoints are not well defined. Using an in vivo Ag-specific adoptive T cell transfer approach into <i>Irf5^−/−</i> mice, we found that T cell–extrinsic IRF5 regulated T cell outcomes at multiple critical checkpoints, including chemokine-mediated T cell trafficking into lymph nodes and PDK1-dependent soluble Ag uptake, costimulatory molecule upregulation, and secretion of Th1 (IL-12)– and Th17 (IL-23, IL-1β, and IL-6)–conditioning cytokines by myeloid cells, which then cross-regulated Th2 and regulatory T cells. IRF5 was required for PRR-induced MAPK and NF-κB activation, which, in turn, regulated these key outcomes in myeloid cells. Importantly, mice with IRF5 deleted from myeloid cells demonstrated T cell outcomes similar to those observed in <i>Irf5^−/−</i> mice. Complementation of IL-12 and IL-23 was able to restore T cell differentiation both in vitro and in vivo in the context of myeloid cell–deficient IRF5. Finally, human monocyte-derived dendritic cells from <i>IRF5</i> disease-associated genetic risk carriers leading to increased IRF5 expression demonstrated increased Ag uptake and increased PRR-induced costimulatory molecule expression and chemokine and cytokine secretion compared with monocyte-derived dendritic cells from low-expressing <i>IRF5</i> genetic variant carriers. These data establish that myeloid cell–intrinsic IRF5 regulates multiple distinct checkpoints in T cell activation and differentiation and that these are modulated by <i>IRF5</i> disease risk variants.