Date of Completion

8-22-2014

Embargo Period

8-22-2014

Keywords

metallothionein, CD4+ T cell activation, zinc, p38, IL-10

Major Advisor

Michael A. Lynes, Ph.D.

Associate Advisor

Adam Zweifach, Ph.D.

Associate Advisor

Lawrence Silbart, Ph.D.

Field of Study

Molecular and Cell Biology

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Metallothioneins (MTs) are small-molecular weight, high cysteine content proteins that bind and release zinc ions in response to redox signaling and oxidative stress. Although the precise cellular functions of MTs remain elusive, their upregulation in CD4+ T cells following activation and during inflammation implicates their role in modulating immune responses. To understand the role of MT in CD4+ T cells, MT expression and [Zn2+] were characterized under different cytokine environments during primary and secondary activation. Increased MT expression correlates with a higher intracellular [Zn2+] following activation, suggesting a potential mechanism of increased MT expression and a role for MT in the differentiation of the CD4+ Tr1 effector phenotype.

CD4+ T cells that do not express MT (MT-KO) exhibit a weaker increase in intracellular labile [Zn2+] following exposure to extracellular ROS or following T cell receptor activation compared with congenic wildtype controls (MT-WT). However, oxidation of ROS sensitive probes is equivalent in the presence or absence of MT, suggesting MT provides a redox sensitive mobilizable zinc reservoir but does not affect the total redox buffering capacity. These results suggest a role for MT in modifying intracellular signal transduction in CD4+ T cells by increasing intracellular [Zn2+] following ROS production.

Download

Share

COinS