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) gamma-deficient mice have hematopoietic defects, some phenotypes of which were microenvironment induced. Bone marrow (BM) microenvironment cells identified by either their expression of nestin (Nes) or osterix (Osx) have previously been shown to have roles in regulating lymphopoiesis. We therefore conditionally deleted Rar gamma in Nes-or Osx-expressing microenvironment cells. Osx cell-specific deletion of Rar gamma had no impact on hematopoiesis. In contrast, deletion of Rar gamma 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 Rar gamma in Nes-expressing cells also had smaller thymi, with reductions in double-negative 4 T cell precursors, accompanied by reduced numbers of both TCR beta(low) immature single-positive CD8(+) cells and double-positive T cells. In the thymus, Nes 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 a and high transcript levels of Rars, Cxcl12, and stem cell factor (Scf). Short-term treatment of mice with all-trans retinoic acid resulted in increased PreB lymphopoiesis in BM and an increase in thymic double-negative 4 T cells, inverse to that observed upon Nes cell-specific deletion of Rar gamma. Collectively, these studies show that RaR gamma is a regulator of B and T lymphopoiesis via Nes-expressing cells in the BM and thymic microenvironments, respectively.