Abstract
Growing evidence suggests that hematopoietic stem/progenitor cells (HSPCs), precursors of mature immune cells, may play a direct role in immunosurveillance. Early myeloid progenitors are the major components of HSPCs and they often undergo extensive expansion in stress as a result of myeloid-biased hematopoiesis. Yet, the precise function of early myeloid progenitors remains unclear. Here we show that during tumor progression, mouse granulocyte/macrophage progenitors (GMPs) but not common myeloid progenitors (CMPs) are markedly expanded within the bone marrow and blood of mice. Interestingly, both GMPs and CMPs freshly isolated from either tumor-bearing or naïve animals are capable of inhibiting polyclonal stimuli- and alloantigen-induced T cell proliferation, with tumor host-derived cells having elevated activities. Strikingly, these early myeloid progenitor cells even display much stronger suppressive capacity than the classical myeloid-derived suppressive cells. Analysis of GMPs indicates that they express iNOS and can secrete high levels of NO. Further studies unusing iNOS specific inhibitors reveal that the immunosuppression of GMPs is, to a large extent, NO-dependent. GMPs can also efficiently induce regulatory T cell development. These studies demonstrate that early myeloid progenitors can act as immunosuppressive cells. This finding provides novel insights into the functional diversity and plasticity of early myeloid progenitor cells.
Highlights
Hematopoietic stem/progenitor cells (HSPCs) are a rare population of precursors responsible for continuous production of blood cells throughout life[1,2]
A typical example for this is the selective expansion of granulocyte/macrophage progenitors (GMPs) occurring in most of primary human CD34+ acute myeloid leukemia (AML) patients[19], which has been recapitulated in AML-modeled mice[20]
We speculate that tumor-derived factors, e.g. GM-CSF25, might act mainly on GMPs causing their differentiation toward myeloid-derived suppressive cells (MDSCs); and as such, amplification of GMPs would further aggravate the augmentation of MDSCs
Summary
Hematopoietic stem/progenitor cells (HSPCs) are a rare population of precursors responsible for continuous production of blood cells throughout life[1,2]. Studies in the past twenty years have characterized well several suppressive myeloid populations, including myeloid-derived suppressive cells (MDSCs)[16], tumor-associated macrophages[17] and regulatory dendritic cells[18] These cell types are generally referred to as regulatory myeloid cells, and all of them have been related to the impaired immune function accompanying stress circumstances. We showed that both GMPs and CMPs (common myeloid progenitors) were able to strongly inhibit polyclonal stimuli- and alloantigen-induced T cell proliferation via distinct mechanisms involving the NO signaling pathway. These studies demonstrated a novel role for early myeloid progenitors, and suggest that immunosuppression might represent a shared functional property for myeloid cells at different stages of differentiation
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