Immunology and Microbiology
First Thesis Advisor
Leslie J. Berg
T cells, Mucosal Immunology, CD4 T helper cells, T helper cell differentiation, PRN694, CD8 T cells, Intestine, Innate Lymphoid Cells, ILC2, Tissue Homeostasis
The Tec kinase ITK is activated by TCR stimulation and also required for TCR downstream signaling. Previous studies have reported differential roles of ITK and another Tec family kinase RLK in CD4+ TH differentiation and effector function. However, these findings are confounded by the complex T cell developmental defects in Itk-/- mice. Furthermore, the function of ITK in tissue-resident T cells in the intestine and anti-viral immune response to a persistent infection has not been studied previously. In addition to T cells, recent studies have indicated an expression of ITK in ILC2, but not in other ILC subsets. Yet, the role of ITK in ILC2 has not been characterized. Here, I have examined the role of ITK and RLK in CD4+ TH subsets using a small molecule inhibitor PRN694. I found that PRN694 impaired TH1 differentiation in vitro, and PRN694 administration prevented TH1-mediated colitis progression in vivo. In an MHV68 infection model, Itk-/- mice failed to control viral replication in the intestine, while gut-homing of CD8+ T cells was greatly impaired. Finally, I found that ILC2 number was markedly reduced in the intestine of Itk-/- mice. Gut-specific defect of Itk-/- ILC2 is associated with a low availability of IL-2 in the intestine of Itk-/- mice. Collectively, these data suggest that ITK is important in T cell migration to the intestine and ILC2 homeostasis in the intestine, thereby contributing to the protective response to a latent virus and intestinal tissue homeostasis.
Cho, H. The Tec kinase ITK is required for homeostasis and anti-viral immune protection in the intestine. (2018). University of Massachusetts Medical School. GSBS Dissertations and Theses. Paper 998. DOI: 10.13028/7r7q-7829. https://escholarship.umassmed.edu/gsbs_diss/998
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