Lewkowich Lab

Current Projects

IL-13 signals through the type 2 IL-4 receptor complex (consisting of IL-4Ra and IL-13Ra1), activating STAT6, while IL-17A signals through a receptor complex consisting of IL-17RA, and IL-17C, activating NF-kB, MAP kinase and C/EBP elements. While the two cytokines utilize distinct receptors and intracellular signaling pathways, we find that IL-17A enhances IL-13 signaling and gene expression.

We are currently working to identify the regions of the IL-13 and IL-17A receptor complexes that are critical for synergy between the two cytokines, and to identify the unique signaling moieties that are activated in the presence of both cytokines. A greater understanding of the molecular mechanisms whereby IL-17A regulates IL-13 signaling may lead to novel therapeutics for the treatment of severe allergic asthma.

In mice that develop a mixed Th2/Th17 immune response after allergen exposure, asthma symptoms are refractory to treatment with steroids. In contrast, in mice that develop a Th2 dominant profile, disease symptoms are completely abrogated by steroids. In both severely and mildly asthmatic mice, Th2 cytokine production is substantially reduced following steroid therapy, demonstrating that both mice strains retain the capacity to respond to steroids. However, while the minimal Th17 cytokine production was completely abrogated in mice with mild asthma, steroids did not significantly inhibit Th17 cytokine production in mice with severe asthma. The data suggest that the Th17 cell is a key player in determining overall sensitivity of allergic asthma to steroids. We are currently working to determine what regulates the steroid sensitivity of Th17 cells, and what factors may be produced by steroid sensitive and steroid refractory Th17 cells that alter the ability of steroids to inhibit their function. A greater understanding of the mechanisms by which Th17 cells resist the inhibitory effects of steroids may have important therapeutic implications for the treatment of severe asthmatics – individuals who are underserved by current therapeutics.

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.