CCL22-Producing CD8α− Myeloid Dendritic Cells Mediate Regulatory T Cell Recruitment in Response to G-CSF Treatment

Abstract

G-CSF prevents type 1 diabetes in the NOD mouse by promoting the local recruitment of T regulatory cells (Tregs). This is an indirect effect because adoptive transfer of G-CSF–induced tolerogenic dendritic cells (DCs) promotes Treg accumulation. However, the identity of the particular DC subset and the molecule(s) mediating this effect remain unknown. We demonstrate in this study that the adoptive transfer of CD11chighCD8α− DCs isolated from pegylated G-CSF (pegG-CSF) recipients, but not that of other DC subtypes, enhanced the pancreatic recruitment of CD4+CD25+Foxp3+ Tregs, which generated increased amounts of TGF-β. Likewise, only CD11chighCD8α− DCs from pegG-CSF recipients secreted the chemokine CCL22 at levels that effectively attracted Tregs. PegG-CSF was more efficient at enhancing the synthesis of CCL22 by CD11chighCD8α− DCs from the pancreatic lymph nodes compared with those from the spleen. Accordingly, CD11chighCD8α− DCs from the pancreatic lymph nodes of pegG-CSF recipients were more efficient than their splenic counterparts in the recruitment of Tregs upon adoptive transfer. Predictably, CD11chighCD8α− DCs failed to recruit these Tregs both in vivo and in vitro following intracellular neutralization of CCL22. These data assign a key role to CD8α− DCs and CCL22 in Treg recruitment in the protection of NOD mice against type 1 diabetes following the treatment with G-CSF.

G-CSF: A Friend or Foe?

“…A causal variant within neutrophil cytosolic factor (NCF2) identified as a susceptibility gene in both childhood-and adult-onset SLE reduced the production of reactive oxygen species (ROS) and enhanced the susceptibility to lupus within patients [96]. This was similar to the association between loss of function polymorphisms in Ncf1 and RA [97][98][99][100][101]. On the other hand, ROS reduction due to Ncf1 deficiency delayed T1D in NOD mice [82], highlighting again the dichotomous function of genes regulating neutrophil activities.…”

Critical role of CCL22/CCR4 axis in the maintenance of immune homeostasis during apoptotic cell clearance by splenic CD8α+CD103+ dendritic cells

“…CCL22, a member of the CC chemokine families, is mainly produced by monocyte-derived macrophages and DCs upon stimulation with microbial products. 32,33 A recent study has reported that the mean serum levels of CCL22 in newly diagnosed patients with multiple sclerosis were significantly lower than those in treated patients with multiple sclerosis and healthy people, 20 suggesting that CCL22 serves as a biomarker for autoimmune diseases. However, the roles of CCL22 in the regulation of immune homeostasis by apoptotic cell clearance are poorly defined, although impairment of apoptotic cell phagocytosis causes autoimmune diseases.…”

CCR2 Influences T Regulatory Cell Migration to Tumors and Serves as a Biomarker of Cyclophosphamide Sensitivity

“…Activation and antigen priming in secondary lymphoid organs promote downregulation of CCR7 and CD62L, whereas other memory/effector type trafficking receptors may be upregulated to allow Tregs to migrate into nonlymphoid or inflamed tissues (14,(17)(18)(19). To date, few chemokine receptors have been associated with the tumor homing properties of Tregs, although a role for CCL22 in the recruitment of CCR4 þ Tregs into human ovarian and/or breast cancer has been described (20)(21)(22).…”