PD-1 is a receptor expressed primarily on T cells that conveys a negative signal into the cell, primarily through dephosphorylating residues normally phosphorylated during T cell activation. The two ligands for PD-1 are PD-L1 (expressed on most nucleated cells) and PD-L2 (expressed primarily by antigen presenting cells, such as dendritic cells, and macrophages). We have found that PD-1/PD-L1 plays a protective role, as blockade of either of these molecules exacerbates asthma development. Interestingly, the increased development of asthma following PD-1 or PD-L1 blockade is associated with increased Th17, but not Th2 immune responses, suggesting that different T cell subsets are differentially susceptible to regulation via the PD-1/PD-L1 axis. In vitro experiments have demonstrated that Th2 cells are resistant to inhibition through PD-1, while Th1 and Th17 cells are sensitive to PD-1 mediated inhibition. This project seeks to identify the mechanisms whereby Th2 cells fail to respond to inhibition via PD-1. A greater understanding of the mechanisms involved in preventing inhibition in response to PD-1 may allow novel therapeutics to enhance the immune response to tumors and during chronic viral infection.
In contrast to the inhibitory role of PD-1 and PD-L1 we have found that PD-L2 plays a pro-asthmatic role, as blockade of this molecule reduces asthma severity. While PD-L2 blockade does increase expression of the Th1-skewing cytokine IL-12, we see little overall impact of PD-L2 blockade on the nature or magnitude of the immune response, suggesting that PD-L2 may regulate asthma development through non-immune pathways. Interestingly PD-L2 was recently shown to interact with an additional ligand, RGMb, a co-factor in the BMP signaling pathway which plays a role in de-differentiation of epithelial cells into more proliferative mesenchymal cells. We are currently exploring the possibility that PD-L2 regulates asthma development through altering the BMP signaling pathways.