Immature myeloid Gr-1+ CD11b+ cells from lipopolysaccharide-immunosuppressed mice acquire inhibitory activity in the bone marrow and migrate to lymph nodes to exert their suppressive function

Abstract

Secondary infections due to post-sepsis immunosuppression are a major cause of death in patients with sepsis.Repetitive inoculation of increasing doses of lipopolysaccharide (LPS) into mice mimics the immunosuppressionassociated with sepsis. Myeloid-derived suppressor cells (MDSCs, Gr-1+ CD11b+) are considered a majorcomponent of the immunosuppressive network, interfering with T-cell responses in many pathological conditions.We used LPS-immunosuppressed (IS) mice to address whether MDSCs acquired their suppressive ability in thebone marrow (BM) and whether they could migrate to lymph nodes (LNs) to exert their suppressive function. Ourresults showed that Gr-1+ CD11b+ cells of IS mice already had the potential to inhibit T-cell proliferation in the BM.Moreover, soluble factors present in the BM from IS mice were responsible for inducing this inhibitory ability incontrol BM cells. In addition, migration of Gr-1+ CD11b+ to LNs in vivo was maximal when cells obtained from theBM of IS mice were inoculated into an IS context. In this regard, we found chemoattractant activity in cell-free LNextracts (LNEs) from IS mice and an increased expression of the LN-homing chemokine receptor C?C chemokinereceptor type 7 (CCR7) in IS BM Gr-1+ CD11b+ cells. These results indicate that Gr-1+ CD11b+ cells found in BMfrom IS mice acquire their suppressive activity in the same niche where they are generated, and migrate to LNs toexert their inhibitory role. A better understanding of MDSC generation and/or regulation of factors able to inducetheir inhibitory function may provide new and more effective tools for the treatment of sepsis-associatedimmunosuppression.