AUTHOR=Sivakumar Ramya , Abboud Georges , Mathews Clayton E. , Atkinson Mark A. , Morel Laurence 

TITLE=Protective Role of Myeloid Cells Expressing a G-CSF Receptor Polymorphism in an Induced Model of Lupus

JOURNAL=Frontiers in Immunology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.01053

DOI=10.3389/fimmu.2018.01053

ISSN=1664-3224

ABSTRACT=<p>The genetic analysis of the lupus-prone NZM2410 mouse has identified a suppressor locus, <italic>Sle2c2</italic>, which confers resistance to spontaneous lupus in combination with NZM2410 susceptibility loci, or in the chronic graft-versus-host disease (cGVHD) induced model of lupus in the B6.<italic>Sle2c2</italic> congenic strain. The candidate gene for <italic>Sle2c2</italic>, the <italic>Csf3r</italic> gene encoding the granulocyte colony-stimulating factor receptor (G-CSF-R/CD114), was validated when cGVHD was restored in B6.<italic>Sle2c2</italic> mice after treatment with G-CSF. The goal of the project reported herein was to investigate the myeloid cells that confer resistance to cGVHD and to ascertain if the mechanism behind their suppression involves the G-CSF pathway. We showed that despite expressing the highest levels of G-CSF-R, neutrophils play only a modest role in the autoimmune activation induced by cGVHD. We also found reduced expression levels of G-CSF-R on the surface of dendritic cells (DCs) and a differential distribution of DC subsets in response to cGVHD in B6.<italic>Sle2c2</italic> versus B6 mice. The CD8α<sup>+</sup> DC subset, known for its tolerogenic phenotype, was expanded upon induction of cGVHD in B6.<italic>Sle2c2</italic> mice. In addition, the deficiency of CD8α<sup>+</sup> DC subset enhanced the severity of cGVHD in B6.<italic>Batf3</italic><sup>−/−</sup> and B6<italic>.Sle2c2</italic> mice, confirming their role in suppression of cGVHD. B6.<italic>Sle2c2</italic>DCs presented lowered activation and antigen presentation abilities and expressed lower levels of genes associated with DC activation and maturation. Exposure to exogenous G-CSF reversed the majority of these phenotypes, suggesting that tolerogenic DCs maintained through a defective G-CSF-R pathway mediated the resistance to cGVHD in B6.<italic>Sle2c2</italic> mice.</p>