Date of Award

2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

Abstract

Antigen stimulation of T lymphocytes induces the activation of phospholipase D (PLD) signaling. Phospholipase D (PLD) is a phosphodiesterase that catalyzes the conversion of phosphatidyl choline (PC) to phosphatidic acid (PA). PA is an important lipid second messenger and is known to mediate a variety of cellular functions. However, the specific role of PA in T lymphocytes has not been established. Previous studies indicated differential requirement for TCR induced PLD signaling in regulatory and non-regulatory T cells. Inhibition of TCR induced PLD signal preferentially suppressed the growth of non-regulatory T cells while allowing the proliferation of regulatory T cells in the presence of exogenous IL-2. Based on this observation, we hypothesized that PLD signaling is a critical factor that balances the population dynamics between regulatory and non-regulatory T cells.

For my dissertation work, I focused on elucidating the functional and molecular regulation of PLD signaling in T cells. In this study, we identified that various exogenous (alcohol and Clostridium difficile toxin) and endogenous factors (adenosine) modulate PLD signaling altering the population dynamics of regulatory and non-regulatory T cells.

PLD has two isoforms namely PLD1 and PLD2 expressed in mammalian cells. These isoforms are 50% identical and have distinct localization in the cell. PLD1 has peri-nuclear localization while PLD2 localizes to the plasma membrane. Molecular analysis of PLD1 and PLD2 using domain deletion suggested that a region unique to PLD1 known as the `loop' confers the distinct peri-nuclear localization of PLD1.

Further, we addressed the specific function of PLD2 in CD4 T cells using PLD2 knock out mice. We found that PLD2 is dispensable for T cell activation and proliferation but might play an important role in effector T cell differentiation. The results from this study delineate some of the functions of PLD signaling in T cells and provide insight into immunological regulation during T cell activation.

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Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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