Nkx2-3 defines the splenic vascular patterning in a lineage-and-dose-dependent manner 9187

Abstract Description The splenic vasculature in both humans and rodents lacks high endothelial venules (HEV) and detectable lymphatic circulation, but it contains an extensive meshwork of red pulp (RP) sinuses, in addition to the marginal sinus (MS) in mice. The complete absence of Nkx2-3 homeodomain transcription factor in mice causes a severe alteration of the splenic structure, including the lack of MAdCAM-1+ MS, defective RP sinus meshwork and the ectopic induction of LYVE-1/Prox1+ lymphatic vessels and PNAd+ HEVs, coupled with impaired humoral immune responses. In this work we investigated the impact of endothelial-restricted lack of Nkx2-3 in VE-cadherin-Cre (Cdh5Cre) and Floxed Nkx2-3 transgenic mice, and also the gene dosage of Nkx2-3 on the splenic vasculature in Nkx2-3+/- mice. We found that in Cdh5Cre:Nkx2-3Fl/Fl mice, the MS-associated marginal reticular cells preserved residual non-endothelial display of MAdCAM-1. In contrast to both wild-type and Nkx2-3 full KO mice, the RP in Cdh5Cre:Nkx2-3Fl/Fl mice contained large clusters of PNAd/MAdCAM+ HEVs. In addition, some ectopic LYVE-1+ lymphatic capillaries were also present, albeit less prominently than in Nkx2-3-/- mice. Nkx2-3+/- spleens also contained ectopic HEVs with similar phenotype to Cdh5Cre:Nkx2-3Fl/Fl, but were devoid of LYVE-1+ lymphatic capillaries. Thus we conclude that the vascular patterning of spleen is fine-tuned by both the lineage-restricted expression of Nkx2-3 and its gene dosage. Funding Sources Supported by NRDIO ADVANCED No.150704 (PB) Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)