GSBS Dissertations and Theses

ORCID ID

0000-0003-0899-8541

Publication Date

2018-10-10

Document Type

Doctoral Dissertation

Academic Program

Immunology and Microbiology

Department

Pathology

First Thesis Advisor

Leslie J. Berg

Keywords

T cells, Mucosal Immunology, CD4 T helper cells, T helper cell differentiation, PRN694, CD8 T cells, Intestine, Innate Lymphoid Cells, ILC2, Tissue Homeostasis

Abstract

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.

DOI

10.13028/7r7q-7829

Rights and Permissions

Copyright is held by the author, with all rights reserved.

Available for download on Monday, April 01, 2019

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