Slc44a2 Deficiency Unveils an IFN‐I–Dependent Feedback Control of pDC Egress

ABSTRACT

Plasmacytoid dendritic cells (pDCs) are a specialized subset of innate immune cells capable of sensing viral nucleic acids and rapidly producing large amounts of type I interferons (IFN‐I). However, excessive IFN‐I production can cause various immunopathogenic conditions. The capacity for IFN‐I production by pDCs is tightly regulated, yet the underlying mechanisms remain incompletely understood. Here, we describe two levels of negative regulatory mechanisms controlling IFN‐I production by pDCs. First, we identified SLC44A2 as a negative regulator of IFN‐I production. Slc44a2 was highly expressed in resting pDCs but significantly downregulated upon activation. Deficiency of Slc44a2 led to excessive IFN‐I production. Mechanistically, SLC44A2 may restrict IFN‐I production by exporting threonine, asparagine, and glutamine, amino acids that we found to be essential for IFN‐I production in pDCs. Second, we uncovered an IFN‐I‐dependent negative feedback mechanism controlling pDC egress. Excessive IFN‐I restrained pDC migration by downregulating CCR2 and CCR5. This feedback was generally observed during viral infections, autoimmune diseases, and in Slc44a2 ‐deficient mice. Taken together, these two regulatory mechanisms are essential for maintaining pDC homeostasis and preventing systemic overactivation of IFN‐I responses.