Inhibition of CD1d-mediated antigen presentation by the TGF-β/Smad signaling pathway (APP3P.113)

Abstract

Abstract CD1d is a MHC class I-like molecule that presents lipid Ags to a subpopulation of innate lymphocytes called natural killer T cells. In a prior study, we showed that the mitogen-activated protein kinase p38 is a negative regulator of Ag presentation by CD1d. It is unknown how p38 is activated to induce this regulation; however, several studies have implicated a role for the immunoregulatory cytokine, TGF-β, in the activation of p38. Therefore, we hypothesized that TGF-β negatively regulates the CD1d-mediated Ag presentation pathway. Indeed, a dose-dependent decrease in CD1d-mediated Ag presentation and impairment of lipid Ag processing was observed in TGF-β-treated antigen presenting cells. However, this inhibition was not through p38 activation. Instead, by employing a lentiviral shRNA-based approach, we found that the canonical TGF-β signaling elements, Smads 2, 3 and 4, contributed to the TGF-β-mediated inhibition of Ag presentation by CD1d. Furthermore, a side-by-side comparative analysis of the effect of TGF-β on CD1d and MHC class II-mediated Ag presentation revealed that in contrast to that observed with CD1d, TGF-β actually enhances MHC class II-mediated Ag presentation. Overall, these results suggest that the canonical TGF-β/Smad pathway has distinctly different effects on the regulation of CD1d- and MHC class II-mediated antigen presentation pathways.