Hal E. Broxmeyer

Vitamin a metabolites induce gut-homing FoxP3+ regulatory T cells

In this study, we report a novel biological function of vitamin A metabolites in conversion of naive FoxP3− CD4+ T cells into a unique FoxP3+ regulatory T cell subset (termed “retinoid-induced FoxP3+ T cells”) in both human and mouse T cells. We found that the major vitamin A metabolite all-trans-retinoic acid induces histone acetylation at the FoxP3 gene promoter and expression of the FoxP3 protein in CD4+ T cells. The induction of retinoid-induced FoxP3+ T cells is mediated by the nuclear retinoic acid receptor α and involves T cell activation driven by mucosal dendritic cells and costimulation through CD28. Retinoic acid can promote TGF-β1-dependent generation of FoxP3+ regulatory T cells but decrease the TGF-β1- and IL-6-dependent generation of inflammatory Th17 cells in mouse T cells. Retinoid-induced FoxP3+ T cells can efficiently suppress target cells and, thus, have a regulatory function typical for FoxP3+ T cells. A unique cellular feature of these regulatory T cells is their high expression of gut-homing receptors that are important for migration to the mucosal tissues particularly the small intestine. Taken together, these results identify retinoids as positive regulatory factors for generation of gut-homing FoxP3+ T cells.

Role of Transforming Growth Factor‐β1 in Regulation of Hematopoiesisab

The data presented above suggest that one possible clinical use of TGF-beta would be to protect the bone marrow from the effects of myelosuppressive chemotherapeutic drugs by preventing entry or removing primitive stem cells from the cell cycle. It may also have the additional benefit of reducing the drug-induced neutrophil nadir by stimulating granulopoiesis. The availability of large quantities of recombinant TGF-beta will allow study of the pharmacokinetics with different routes of administration, dosage effects, and details of the pleiotropic effects on other cell systems. Experiments are in progress to determine whether TGF-beta will allow the delivery of higher amounts or more frequent doses of chemotherapeutic drugs and thus allow increased antitumor efficacy in tumor-bearing animals.

AMD3100 ameliorates cigarette smoke-induced emphysema-like manifestations in mice

We have shown that cigarette smoke (CS)-induced pulmonary emphysema-like manifestations are preceded by marked suppression of the number and function of bone marrow hematopoietic progenitor cells (HPCs). To investigate whether a limited availability of HPCs may contribute to CS-induced lung injury, we used a Food and Drug Administration-approved antagonist of the interactions of stromal cell-derived factor 1 (SDF-1) with its chemokine receptor CXCR4 to promote intermittent HPC mobilization and tested its ability to limit emphysema-like injury following chronic CS. We administered AMD3100 (5mg/kg) to mice during a chronic CS exposure protocol of up to 24 wk. AMD3100 treatment did not affect either lung SDF-1 levels, which were reduced by CS, or lung inflammatory cell counts. However, AMD3100 markedly improved CS-induced bone marrow HPC suppression and significantly ameliorated emphysema-like end points, such as alveolar airspace size, lung volumes, and lung static compliance. These results suggest that antagonism of SDF-1 binding to CXCR4 is associated with protection of both bone marrow and lungs during chronic CS exposure, thus encouraging future studies of potential therapeutic benefit of AMD3100 in emphysema.

Regulation of Constitutive Tip110 Expression in Human Cord Blood CD34+ Cells Through Selective Usage of the Proximal and Distal Polyadenylation Sites Within the 3′Untranslated Region

Tip110 plays important roles for stem cell pluripotency and hematopoiesis. However, little is known about the regulatory mechanisms of Tip110 expression in this process. In this study, we first showed that constitutive Tip110 expression was cell proliferation and differentiation dependent and self-regulated in both human cord blood CD34+ cells. Using a series of molecular techniques, we found that ectopic Tip110 expression led to increased constitutive Tip110 expression through its 3-untranslated region (3UTR), specifically through preferential usage of proximal polyadenylation sites within its 3UTR in cells, including human cord blood CD34+ cells, which indeed led to an increased number of CD34+ cells during differentiation of those cells. Lastly, we showed that Tip110 protein interacted with cleavage stimulation factor 64 (CstF64) protein and that more CstF64 was recruited to the promixal polyadenylation site than the distal polyadenylation site within its 3UTR. These finding together demonstrates that constitutive Tip110 expression is regulated, at least in part, through its interaction with CstF64, recruitment of CstF64 to, and selective usage of those two polyadenylation sites within its 3UTR.