Date of Final Oral Examination (Defense)

12-2009

Type of Culminating Activity

Thesis

Degree Title

Master of Science in Biology

Department

Biology

Major Advisor

Dr. Denise Wingett

Abstract

Diesel exhaust particles (DEP) represent a key component of particulate matter pollution and a serious cardiopulmonary health risk, as these particles have been associated with increased morbidity and mortality following exposure. In this study, we investigated the immunomodulatory properties of DEP on helper T cells by measuring changes in activation, cytokine production, and viability. The expression of CD40L, a key regulatory protein, was increased by DEP in the absence of physiologic stimuli without parallel increases in the expression of CD25 and CD69 activation markers. Additional studies utilizing a variety of T cell stimuli, including T cell receptor signaling and CD28 construction, showed consistent and reproducible increases in the expression of CD40L with negligible effects on other activation markers. Further studies demonstrated that the ability of DEP to augment CD40L production was restricted to the induction of the membrane-bound form of this protein, as soluble CD40L (sCD40L) was generally decreased. However, an increase in both membrane and sCD40L was observed in the context of cAMP signaling, which may have implications for at-risk populations utilizing the therapeutic effects of this important second messenger, including beta (ß)- adrenergic agonists bronchodilators for the treatment of respiratory disease. Additional studies were performed to evaluate changes in the production of IL-8 and IL-17 cytokines. DEP produced no appreciable effect on IL-8 generation, but inhibited the production of IL-17. Evaluation of cytotoxicity indicated DEP had no measurable effect on T cell viability in resting cells. Collectively, these findings demonstrate an innmunomodulatory capacity of DEP and may, in part, provide a mechanism explaining the contributions of DEP to the observed changes in morbidity and mortality. Given the importance of CD40L signaling in normal immune function, the findings that CD40L expression was increased regardless of the cellular activation status may be very relevant to diseases where the immune system contributes to pathogenic processes.

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