Retinoic acid receptor γ regulates B and T lymphopoiesis via nestin-expressing cells in the bone marrow and thymic microenvironments

Vitamin A has essential but largely unexplained roles in regulating lymphopoiesis. We have previously shown that retinoic acid receptor (RAR) γ-deficient mice have hematopoietic defects, some phenotypes of which were microenvironment induced. Bone marrow (BM) microenvironment cells identified by either their expression of <i>nestin</i> (<i>Nes</i>) or <i>osterix</i> (<i>Osx</i>) have previously been shown to have roles in regulating lymphopoiesis. We therefore conditionally deleted <i>Rarγ</i> in <i>Nes-</i> or <i>Osx-</i>expressing microenvironment cells. <i>Osx</i> cell-specific deletion of Rarγ had no impact on hematopoiesis. In contrast, deletion of <i>Rarγ</i> in Nes-expressing cells resulted in reductions in peripheral blood B cells and CD4⁺ T cells, accompanied by reductions of immature PreB cells in BM. The mice lacking <i>Rarγ</i> in <i>Nes-</i>expressing cells also had smaller thymi, with reductions in double-negative 4 T cell precursors, accompanied by reduced numbers of both TCRβ^low immature single-positive CD8⁺ cells and double-positive T cells. In the thymus, <i>Nes</i> expression was restricted to thymic stromal cells that expressed cerebellar degeneration-related Ag 1 and lacked expression of epithelial cell adhesion molecule. These cells expressed platelet-derived growth factor α and high transcript levels of <i>Rars</i>, <i>Cxcl12</i>, and <i>stem cell factor</i> (<i>Scf</i>). Short-term treatment of mice with all-<i>trans</i> retinoic acid resulted in increased PreB lymphopoiesis in BM and an increase in thymic double-negative 4 T cells, inverse to that observed upon <i>Nes</i> cell-specific deletion of <i>Rarγ</i>. Collectively, these studies show that <i>RARγ</i> is a regulator of B and T lymphopoiesis via <i>Nes-</i>expressing cells in the BM and thymic microenvironments, respectively.