Abstract
BackgroundIt has been reported that human FOXP3+ CD4 Tregs express GARP-anchored surface latency-associated peptide (LAP) after activation, based on the use of an anti-human LAP mAb. Murine CD4 Foxp3+ Tregs have also been reported to express surface LAP, but these studies have been hampered by the lack of suitable anti-mouse LAP mAbs.Methodology/Principal FindingsWe generated anti-mouse LAP mAbs by immunizing TGF-β−/− animals with a mouse Tgfb1-transduced P3U1 cell line. Using these antibodies, we demonstrated that murine Foxp3+ CD4 Tregs express LAP on their surface. In addition, retroviral transduction of Foxp3 into mouse CD4+CD25− T cells induced surface LAP expression. We then examined surface LAP expression after treating CD4+CD25− T cells with TGF-β and found that TGF-β induced surface LAP not only on T cells that became Foxp3+ but also on T cells that remained Foxp3− after TGF-β treatment. GARP expression correlated with the surface LAP expression, suggesting that surface LAP is GARP-anchored also in murine T cells.Conclusions/SignificanceUnlike human CD4 T cells, surface LAP expression on mouse CD4 T cells is controlled by Foxp3 and TGF-β. Our newly described anti-mouse LAP mAbs will provide a useful tool for the investigation and functional analysis of T cells that express LAP on their surface.
Highlights
TGF-b controls immune responses by multiple mechanisms including the suppression of Th1 and cytotoxic lymphocytes, and the induction of Th17 cells depending on the context [1]
Surface expression of murine latency-associated peptide (LAP) was expected on P3U1-muTGF-b cells since we found that antiTGF-b surface stained P3U1-muTGF-b cells as well as P3U1-huTGF-b cells (Figure S1)
As a part of our investigation of TGF-b, we found that the anti-human LAP mAb 27232 used by Nakamura et al does not cross-react with mouse LAP (Figure S1)
Summary
TGF-b controls immune responses by multiple mechanisms including the suppression of Th1 and cytotoxic lymphocytes, and the induction of Th17 cells depending on the context [1]. Expression of pro-TGF-b, LAP, latent TGF-b and/or mature TGF-b (hereafter referred as LAP/TGF-b) on mouse CD4 T cells was first reported in 2001 by Nakamura et al [3]. They proposed that CD4+CD25+ regulatory T cells (Tregs) mediated their suppressive function by presenting active TGF-b to effector cells in a cell-cell contact manner. They used a polyclonal chicken antiTGF-b antibody and a monoclonal anti-human LAP mAb (clone 27232) for FACS staining of mouse CD4 T cells. Murine CD4 Foxp3+ Tregs have been reported to express surface LAP, but these studies have been hampered by the lack of suitable anti-mouse LAP mAbs
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