The Size of the Plasmacytoid Dendritic Cell Compartment Is a Multigenic Trait Dominated by a Locus on Mouse Chromosome 7

Abstract

Plasmacytoid dendritic cells (pDC) compose one of the many distinct dendritic cell subsets. The primary function of pDC is to potently produce type 1 IFNs upon stimulation, which is highly relevant in antiviral responses. Consequently, the ability to manipulate the size of the pDC compartment in vivo may increase the capacity to clear viral infections. In an attempt to identify genetic loci affecting the size of the pDC compartment, defined by both the proportion and absolute number of pDC, we undertook an unbiased genetic approach. Linkage analysis using inbred mouse strains identified a locus on chromosome 7 (Pdcc1) significantly linked to both the proportion and the absolute number of pDC in the spleen. Moreover, loci on either chromosome 11 (Pdcc2) or 9 (Pdcc3) modified the effect of Pdcc1 on chromosome 7 for the proportion and absolute number of pDC, respectively. Further analysis using mice congenic for chromosome 7 confirmed Pdcc1, demonstrating that variation within this genetic interval can regulate the size of the pDC compartment. Finally, mixed bone marrow chimera experiments showed that both the proportion and the absolute number of pDC are regulated by cell-intrinsic hematopoietic factors. Our findings highlight the multigenic regulation of the size of the pDC compartment and will facilitate the identification of genes linked to this trait.

Anatomical distribution analysis reveals lack of Langerin+ dermal dendritic cells in footpads and tail of C57BL/6 mice

“…Such differences among skin DC subsets are reminiscent of mouse-strain-specific expression of the endocytic receptor Langerin by LN-resident CD8+ DCs and gut DCs (21,22), and by the variations of plasmacytoid DC numbers linked to genetic polymorphisms (23,24). Footpads and the tail have a particularly protective stratum corneum, which might explain why immunosurveillance does not necessarily require the highly immunocompetent Langerin+ dDCs.…”

“…There are reports showing the generation of free radicals during melanogenesis which hydroxylate tyrosinase and other proteins, thereby increasing their antigenicity (22,23). Elassiuty et al, showed upregulation of heme oxygenase-1 in patients' melanocytes due to high oxidative stress (24). The build-up of ROS along with possible immune system defects allows for the inappropriate autoimmune response against melanocytes.…”

Plasmacytoid dendritic cells from parent strains of the NZB/W F1 lupus mouse contribute different characteristics to autoimmune propensity

“…pDCs are major producers of IFNα . It has been noted that different mouse strains vary in capacity of IFNα production . We and others had recently found that pDCs from NZB/W F1 mice produce more IFNα in vitro than those from C57BL/6 mice .…”

“…5 It has been noted that different mouse strains vary in capacity of IFNa production. 17,18 We and others had recently found that pDCs from NZB/W F1 mice produce more IFNa in vitro than those from C57BL/6 mice. 19,20 Here we revealed further that between the two parent strains, NZW pDCs are the potent producers of IFNa than NZB pDCs.…”

“…Comparison of pDCs among different laboratory mouse strains revealed that different mouse strains vary in pDC abundance and IFNa production. 17,18 Of note, the higher production of IFNa in response to CpG observed with some mouse strains was not a result of an intrinsic higher ability of pDC, rather it reflected the higher abundance of spleen pDCs in the mouse strain. 17 We and others had recently found that pDCs from NZB/W F1 mice produce more IFNa in vitro as it confers a survival advantage, compared with those from C57BL/6 mice.…”