Th2 cells are central to the disease pathology of allergic asthma, however other T cell subsets play a disease- modifying role: Tregs limit asthma development, while Th17 cells and particularly pathogenic Th2/Th17 cells are associated with more severe disease. A key question remains how genetic alterations affect differentiation of T helper cells and contribute to asthma. Recently, a SNP in the GTPase of immunity-associated protein-5 (GIMAP5) were found to associate with increased asthma development. GIMAP5 is essential for peripheral lymphocyte survival and function; however, the underlying mechanism(s) and the biological function of GIMAP5 remain entirely elusive. Our new studies confirm the critical role for Gimap5 in allergic asthma, with Gimap5- deficient mice having significantly increased airway hyperresponsiveness (AHR), lung inflammatory cell infiltration upon house dust mite (HDM) challenge. Importantly, Gimap5-deficient mice progressively lose Treg function, cannot develop inducible Treg cells, and exhibit impaired T cell proliferation, while remaining CD4+ T cells are strongly skewed towards Th17 differentiation. When challenged with HDM, Gimap5-deficient mice develop a marked increase in pathogenic Th2/Th17 CD4+ T cells. Our new mechanistic data suggest that Gimap5 is essential for the inhibition of Glycogen Synthase Kinase-3 (GSK3)?a serine/threonine protein kinase whose inhibition is essential for the expression/activation of transcription factors required for T cell proliferation/differentiation. Importantly, pharmacological/genetic targeting of GSK3 completely recovers T cell survival/proliferation in Gimap5-deficient mice. These data support the overall hypothesis that loss of Gimap5 in CD4+ T cells promotes Th17/Th2 development at the expense of Tregs, thereby exacerbating asthma development. This will be tested in 2 independent yet interrelated aims using both mouse models and analysis of human sera from patients with allergic disease.
Aim 1 will test the hypothesis that Gimap5 LOF exacerbates asthma by promoting the development of pathogenic Th2/Th17 cells at the expense of Treg cells, while aim2 will test the hypothesis that inhibiting GSK3 activity will prevent the skewing of Th2/Th17 differentiation away from Tregs that leads to severe allergic airway disease in Gimap5-deficient mice.
Gimap5 is predominantly expressed in lymphocytes, however, it's function remains largely unknown. Recently, SNPs in Gimap5 have been associated with increased risk for asthma. The current proposal aims to study the functional role of Gimap5 in CD4+ T cell differentiation and asthma development, while investigating the association between the human risk allele in Gimap5 and Th2/Th17 cytokine levels in patients. Our studies are not only critical for understanding the role of Gimap5 in asthma development, but will also test new therapeutic approaches.
