Abstract
Early innate education of hematopoietic progenitors within the bone marrow (BM) stably primes them for either trained immunity or instead immunoregulatory functions. We herein demonstrate that in vivo or in vitro activation within the BM via Toll-like receptor-9 generates a population of plasmacytoid dendritic cell (pDC) precursors (CpG-pre-pDCs) that, unlike pDC precursors isolated from PBS-incubated BM (PBS-pre-pDCs), are endowed with the capacity to halt progression of ongoing experimental autoimmune encephalomyelitis. CpG activation enhances the selective migration of pDC precursors to the inflamed spinal cord, induces their immediate production of TGF-β, and after migration, of enhanced levels of IL-27. CpG-pre-pDC derived TGF-β and IL-27 ensure protection at early and late phases of the disease, respectively. Spinal cords of CpG-pre-pDC-protected recipient mice display enhanced percentages of host-derived pDCs expressing TGF-β as well as an accumulation of IL-10 producing B cells and of CD11c+ CD11b+ dendritic cells. These results reveal that pDC precursors are conferred stable therapeutic properties by early innate activation within the BM. They further extend to the pDC lineage promising perspectives for cell therapy of autoimmune diseases with innate activated hematopoietic precursor cells.
Highlights
Innate education of hematopoietic progenitors within the bone marrow (BM) stably primes them for either trained immunity or instead immunoregulatory functions
CD45.1 adoptively transferred CpG-pre-plasmacytoid dendritic cell (pDC) retained their significantly reduced IRF7 expression after migrating to the spinal cord in CD45.2 recipients (Fig. 3d,e), as compared to host CD45.2 PDCA-1+ cells in the same tissue in CD45.2 recipients and to CD45.2 PDCA-1+ cells in control mice with EAE injected with PBS medium only
In keeping with reports showing that GM-CSF, here produced by both migrated CpG-pre-pDCs and CD4+ T-cells in their recipients, may exert regulatory effects by triggering accumulation of IL-10 producing B-cells (B10)[33,34] and of C D11c+CD11b+ tolerogenic D Cs35,36, we found that these populations were significantly accumulated in the spinal cord of CpG-pre-pDC recipients compared to controls for the B10 (Fig. 4d) and to both controls and PBS-pre-pDC recipients for the DCs (Fig. 4e,f)
Summary
Innate education of hematopoietic progenitors within the bone marrow (BM) stably primes them for either trained immunity or instead immunoregulatory functions. Spinal cords of CpG-pre-pDC-protected recipient mice display enhanced percentages of host-derived pDCs expressing TGF-β as well as an accumulation of IL-10 producing B cells and of CD11c+ CD11b+ dendritic cells These results reveal that pDC precursors are conferred stable therapeutic properties by early innate activation within the BM. (f) Intracytoplasmic TGF-β expression was analyzed by FACS in PBS- and CpG-pre-pDCs. One experiment out of two (g) IFN-α production was measured by ELISA in supernatants of CpG- versus PBS-induced cell-sorted c-kit+Sca1+B220intPDCA-1+ BM cells after 18 h incubation with 1 μg/ml TLR-7 (R848), TLR-9 (CpG-B and CpG-P) and TLR-4 (LPS) agonists (biological duplicates). CpG-proBs have the capacity to migrate towards the immune reaction site and target tissues, where they differentiate into diverse mature Breg subsets that act locally[9] These observations suggested that early education of hematopoietic progenitors within the BM may be essential to imprint regulatory functions that enable them to control immune responses in the periphery
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