Biomedical Sciences ETDs

Katy Korzekwa

Publication Date

7-1-2012

Abstract

T cells are critical players in adaptive immunity. They migrate throughout the body scanning the lymph nodes for antigen, then migrate to an infection site to help clear pathogen. Migrating T cells use multiple receptors and adhesion proteins to migrate to and enter different tissues. While the cell surface molecules involved in T cell motility are well understood, less is known about intracellular signaling pathways involved in T cell migration. PKCθ and CARMA1 signal downstream of TCR activation to induce NF-κB activation. However, the roles of PKCθ and CARMA1 in other T cell functions are unknown. In this study we investigate the roles of PKCθ and CARMA1 in regulating T cell migration. We found that CARMA1 deficiency led to defective regulation of cell surface adhesion molecules, increased migration speed of activated T cells in vitro, and mislocalization of the actin regulatory ERM proteins. In contrast, PKCθ deficiency did not affect the regulation of adhesion molecules or the migration of T cells. However PKCθ-/- T cells also showed mislocalization of ERM proteins. Although CARMA1 is directly phosphorylated downstream of PKCθ following TCR activation, our data show that CARMA1 likely regulates T cell migration in a PKCθ independent manner. We also investigated the role of PKCθ in immunity to infection with the intracellular bacteria Francisella tularensis. PKCθ is important in immunity to some pathogens, but in certain cases, PKCθ deficiency is not important or can even be protective. T cells are crucial in F. tularensis immunity, with multiple subsets playing an important role. We found that PKCθ deficiency was protective against LVS, an F. tularensis strain highly infectious in mice, with PKCθ-/- mice surviving longer than the WT mice upon LVS infection. We found the organs of the infected PKCθ-/- mice had a smaller percentage of CD4+ T cells and a larger percentage of CD4-CD8- T cells compared to WT mice. These results suggest that PKCθ-/- mice are protected against F. tularensis infection and that PKCθ may contribute to the development of different T cell populations which contribute to protective immunity against F. tularensis infection.

Keywords

T cells, CARMA1, PKC╬╕, migration, Francisella

Document Type

Thesis

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Masters

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Mold, Carolyn

Second Committee Member

Wilson, Bridget

Third Committee Member

Wu, Terry

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