Abstract
Microbial recognition by pattern recognition receptors (PRRs) expressed on hematopoietic stem and progenitor cells (HSPCs) not only activates myelopoiesis but also programs the function of the monocytes and macrophages they produce. For instance, changes in HSPC programming modify the ability of macrophages derived from them to produce inflammatory cytokines. While HSPCs exposed to a TLR2 agonist give rise to tolerized macrophages (lower proinflammatory cytokine production), HSPCs treated with Dectin-1 ligands produce trained macrophages (higher proinflammatory cytokine production). However, nothing is known about the impact of HSPC exposure to microbes on the function of antigen presenting cells (APCs). In this study we evaluated whether treatment of murine bone marrow HSPCs with a TLR2 or Dectin-1 ligand impacts the antigen presenting capacity of APCs derived from them in vitro. Following activation with microbial ligands or Candida albicans yeasts, APCs derived from TLR2/Dectin-1-programed HSPCs exhibit altered expression of MHCII (signal 1), co-stimulatory molecules (CD40, CD80 and CD86; signal 2) and cytokines (TNF-α, IL-6, IL-12 p40 and IL-2; signal 3). Moreover, APCs derived from TLR2/Dectin-1-programed HSPCs prime enhanced Th1 and Th17 responses, which are important for antifungal defense, in CD4 T cell cocultures. Overall, these results demonstrate for the first time that microbial detection by bone marrow HSPCs can modulate the adaptive immune response by inducing the production of APCs with an altered phenotype.
Highlights
Hematopoietic stem and progenitor cells (HSPCs) are increasingly being appreciated to be important players in the fight against microbial infections, due to their ability to produce more innate immune cells to replace those consumed during the infection process and boost the number of responding cells
We evaluated whether in vitro treatment of murine bone marrow hematopoietic stem and progenitor cells (HSPCs) with a TLR2 or Dectin-1 ligand impacts the function of the antigen presenting cells (APCs) derived from them
We decided to study whether stimulation of HSPCs with Dectin-1 or TLR2 ligands could alter the functional phenotype of the APCs derived from them and subsequently have an impact in T
Summary
Hematopoietic stem and progenitor cells (HSPCs) are increasingly being appreciated to be important players in the fight against microbial infections, due to their ability to produce more innate immune cells to replace those consumed during the infection process and boost the number of responding cells. TLR2 and Dectin-1 signaling instruct very different functional programing in HSPCs. HSPCs treated in vitro with Pam CSK4 (a TLR2 agonist) give rise to macrophages with a reduced ability to produce inflammatory cytokines (tolerized response) [4]. HSPCs treated in vitro with β-glucans (a Dectin-1 agonist found in the cell wall of fungi) or whole C. albicans yeasts give rise to macrophages with an enhanced ability to produce inflammatory cytokines (trained response) [5]. Macrophages derived from HSPCs exposed to microbial ligands display changes in their functional phenotype These data indicate that innate immune memory, which has been described in monocytes and results from long-lasting epigenetic and metabolic changes that alter their functional properties, occurs in HSPCs, and this phenomenon might contribute to the durability of innate immune memory [6]. Consistent with this, in vivo studies have demonstrated that β-glucans and the Bacillus Calmette-Guérin (BCG) vaccine impact progenitor programming and train monocyte and macrophage responses, and most importantly, have shown that trained HSPCs have the capacity to induce heterologous protection against secondary infections [7,8,9]
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