The non-canonical Wnt pathway negatively regulates dendritic cell differentiation by inhibiting the expansion of Flt3+ lymphocyte-primed multipotent precursors

Abstract

The differentiation of dendritic cells (DC) is affected by the aging process. However, the molecular mechanisms responsible for the alteration of DC development in aged mice have not been clarified. Recently, Wnt5a was reported to be an important aging-related molecule in hematopoietic systems. Here, we hypothesized that the increased expression of Wnt5a in aged hematopoietic precursors led to deficient DC differentiation in aged mice. The percentages and cell numbers of plasmacytoid DC (pDC) and CD172a 2 CD8a 1 conventional DC (cDC) were decreased in aged mice compared to young mice. Further analysis indicated that the hematopoietic precursors that gave rise to DC, including Flt3 1 lymphoid-primed multipotent precursors (LMPP), common lymphoid progenitors (CLP) and common DC precursors (CDP), were all decreased in the bone marrow of aged mice. Overexpression of Wnt5a in hematopoietic precursors strongly affected the differentiation of cDC and pDC in vivo. Treatment of hematopoietic stem cells (HSC) with Wnt5a led to a significant decrease in the differentiation of the LMPP, CLP and CDP populations that was similar to the decrease observed in the bone marrow (BM) HSC of aged mice. Molecular studies demonstrated that Wnt5a negatively regulated the expression of an array of genes important for DC differentiation, including Flt3, Gfi-1, Ikaros, Bcl11a, and IL-7R, by activating the Wnt5a-Cdc42 pathway. Finally, we rejuvenated DC differentiation from aged precursors by blocking the non-canonical Wnt pathway. Our study identified the key roles of the non-canonical Wnt pathway in DC differentiation and DC aging. Cellular & Molecular Immunology

Progressive alterations in multipotent hematopoietic progenitors underlie lymphoid cell loss in aging

“…Downstream lymphoid-committed progenitors including common lymphoid progenitors (CLPs) and common dendritic cell progenitors (CDPs) are depleted with aging ( Miller and Allman, 2003 ; Min et al, 2006 ; Grover et al, 2016 ; Xiao et al, 2016 ). We observed significant decreases in BM frequency of CLPs and M-CSFR − CDPs at 14 and 28 mo, respectively ( Fig.…”

Human Regulatory T Cells Mediate Transcriptional Modulation of Dendritic Cell Function

“…Wnt5a is one of the most extensively studied Wnt family members and is known to play an important role in many developmental processes, including differentiation of human monocytes to DC (26). Growing evidence points to Wnt5a as a negative regulator of DC differentiation (16,27) demonstrating that Wnt5a expression can skew differentiation to a more tolerogenic functional state in both DCs (15,28) and macrophages (16). Increased Wnt5a signaling in monocyte-derived DCs has led to their reduced ability in dextran uptake as well as reduced surface expression of costimulatory molecules with compromised functional capacity (15), results similar to our findings of Treg-modulation of DCs.…”

Mechanisms by Which Dendritic Cells Present Tumor Microparticle Antigens to CD8+ T Cells

“…1I). We additionally analyzed the Flt3L-induced DCs and CD8a þ DCs isolated from the spleen (19)(20)(21)(22). These DCs induced OT-1 T-cell proliferation and IFNg production after OVA-MPs pulsing (Supplementary Fig.…”