Regulation of Airway Tolerance and Antigen-specific Regulatory T cells by the Costimulatory Molecule OX40 (88.39)

Abstract

Abstract Respiratory exposure to soluble antigen leads to airway tolerance and antigen-specific suppression of airway inflammation. There is increasing evidence that this involves inducible regulatory T cells (Treg) that suppress pathogenic Th2 cells. What controls Treg activity is not clear. We investigated the role of the costimulatory molecule OX40 in the generation and function of Foxp3+ Treg induced by soluble OVA, given either intravenously or intranasally. By tracking adoptively transferred OVA-specific CD4 cells, we observed that markedly fewer Foxp3+ cells were induced in the absence of OX40, suggesting OX40 can control their expansion and/or survival. Also, already generated OVA-specific CD4 Foxp3+ cells when adoptively transferred into sensitized mice, suppressed lung inflammation. This suppression was impaired if the Treg lacked OX40, further demonstrating that OX40 can positively control the function of this Treg subset. In contrast, we found that an OX40 agonist antibody reversed established airway tolerance when given with antigen immunization, implying that anti-OX40 either augmented Th2 cell expansion or inhibited Treg. Thus, OX40 signals can positively affect inducible Treg but they might equally control pathogenic T cell activity. These studies further substantiate the idea that OX40 is central to the activities of several subsets of T cells that control airway inflammation.