Prolactin Acts on Myeloid Progenitors to Modulate SMAD7 Expression and Enhance Hematopoietic Stem Cell Differentiation into the NK Cell Lineage

Abstract

Numerous cell types modulate hematopoiesis through soluble and membrane bound molecules. Whether developing hematopoietic progenitors of a particular lineage modulate the differentiation of other hematopoietic lineages is largely unknown. Here we aimed to investigate the influence of myeloid progenitors on CD34 + cell differentiation into CD56 + innate lymphocytes. Sorted CD34 + cells cultured in the presence of stem cell factor (SCF) and FMS-like tyrosine kinase 3 ligand (FLT3L) give rise to numerous cell types, including progenitors that expressed the prolactin receptor (PRLR). These CD34 + pRLR + myeloid-lineage progenitors were derived from granulocyte monocyte precursors (GMPs) and could develop into granulocytes in the presence of granulocyte-macrophage colonystimulating factor (GM-CSF) in vitro. Moreover, CD34 + pRLR + myeloid progenitors lacked lymphoid developmental potential, but when stimulated with prolactin (PRL) they increased the differentiation of other CD34 + cell populations into the NK lineage in a non-contact dependent manner. Both mRNA and protein analyses show that PRL increased mothers against decapentaplegic homolog 7 (SMAD7) in CD34 + pRLR + myeloid cells, which reduced the production of transforming growth factor beta 1 (TGF-β1), a cytokine known to inhibit CD56 + cell development. Thus, we uncover an axis whereby CD34 + pRLR + GMPs inhibit CD56 + lineage development through TGF-β1 production and PRL stimulation leads to SMAD7 activation, repression of TGF-β1, resulting in CD56 + cell development. Hematopoietic differentiation is specified by a multitude of soluble and membrane-bound molecules produced both within and outside of the hematopoietic system that influence cell fate decisions 1-6. In line with this, numerous cytokines including interleukin (IL)-1, IL-2, IL-7, IL-12, IL-15, IL-18, IL-21, IL-23, IL-25 and IL-33 have been shown to modulate the development of NK cells and other innate lymphoid cells (ILCs) 7-14. Moreover, NK cells and other ILCs require different transcription factors such as Tbet, RORc and Gata3 for their development 7,15,16. Multi-lymphoid progenitor (MLP) differentiate into the common ILC progenitor and this cell then gives rise to NK cells and all helper ILCs (i.e., ILC1, 2 and 3) 12-14,17. NK cells and helper ILCs are distinguished by specific transcription factor expression, cytokine production and function 9,13,14,18,19. We have used in vitro differentiation to study these processes and over the last decade have found that both NK cells and helper ILCs (particularly, ILC1s and ILC3s) develop in this system and similarly express CD56 16,20-23. Therefore, throughout this manuscript we use the term CD56 + lymphocytes to describe all CD56 expressing cells. Prolactin (PRL) is a neuroendocrine hormone best known for its role in lactation. However, PRL also regulates hematopoietic cell development and homeostasis 24-28. Specifically, PRL enhances the development of myeloid and

Prolactin Increases the Frequency of Follicular T Helper Cells with Enhanced IL21 Secretion and OX40 Expression in Lupus-Prone MRL/lpr Mice

“…The costimulatory roles of PRL in the in vitro activation of T cells and B cells have been previously reported [5,64]. In addition, PRL promotes differentiation into CD4 + T-bet + T cells [12], CD4 + Eomes + T cells [6], and NK cells [8]. T FH cells have a higher expression of the receptor with respect to T naïve cells.…”

“…The neuroendocrine and immune systems are closely interrelated, as the secretory products of the neuroendocrine system can act on the immune system and vice versa [1]. One example involves hormones that can regulate the immune system [2,3], such as prolactin (PRL) secreted by the pituitary gland, and extrapituitary immune system cells, such as T cells [4,5], B cells, antigen presenting cells (APCs) [6], natural killer cells [7,8], and monocytes/macrophages [9]. The immunostimulatory functions of PRL have been previously described.…”

Resilience in Long-Term Viral Infection: Genetic Determinants and Interactions

“…GDF9 regulates ovarian function [ 72 , 73 ]. PRL, meanwhile, is also a growth regulator, including for the immune system (for example, [ 74 , 75 ]).…”

The effect of prolactin on immune cell subsets involved in SLE pathogenesis

“…It enhances an inflammatory response. (118)(119)(120)(121) the other hand, the number of NK cells expressing PD1 and T-cell-induced negative regulator TIM-3 significantly increases in SLE. Furthermore, this increase correlates with worsened erythrocyte sedimentation rate and increased Creactive protein and anti-dsDNA autoantibody levels.…”