Surfactant Protein-A modulates induction of regulatory T cells in the lung via TGFβ (168.8)

Abstract TCR signaling plays a critical role in regulatory T cell (Treg) development. However, the mechanism for tissue specific induction of Tregs in the periphery remains unclear. Surfactant protein A (SP-A) is a major immune defense protein in the lung. To determine if SP-A contributes to the normal non-inflammatory status mediated by Tregs in the lung, T cells were activated with various stimuli. Compared to WT mice, on ex vivo culture, T cells from lungs of SP-A deficient mice have impaired expression of Foxp3 and fewer CD25+Foxp3+ Treg phenotype cells. These phenotypic effects could be rescued by the addition of exogenous SP-A. Even as cell cycle progression is blocked, both IL-2 levels as well as active TGFβ levels increase on extended culture. In addition, kinetic suppression assays demonstrate that SP-A enhances the frequency of functional Foxp3+Tregs in responder T cell populations in a TGFβ dependent manner. To induce Tregs in the lung in vivo, we modified the extended LPS model described by d’Alessio et al (1). While the proportion of Tregs increased ≈160% in WT mice ~8d post-exposure, SP-A-/- mice showed a much more modest 50% increase over their near identical baselines. We also observed a strong correlation between FR4 and Foxp3 expression in functional Tregs induced by SP-A. Together, these findings suggest that SP-A exerts long-term effects on T cell immune function by the induction of Tregs during activation. (1) D’Alessio et al J Clin Invest. (2009) 119: 2898