Regulation of T cell receptor CD3zeta chain expression by L-arginine

Abstract

L-Arg plays a central role in the normal function of several organ systems including the immune system. L-Arg can be depleted by arginase I produced by macrophages and hepatocytes in several disease states such as trauma and sepsis and following liver transplantation. The decrease in L-Arg levels induces a profound decrease in T cell function through mechanisms that have remained unclear. The data presented here demonstrate that Jurkat T cells cultured in medium without L-Arg (L-Arg-free RPMI) have a rapid decrease in the expression of the T cell antigen receptor zeta chain (CD3zeta), the principal signal transduction element in this receptor, and a decrease in T cell proliferation. This phenomenon is completely reversed by the replenishment of L-Arg but not other amino acids. These changes are not caused by cell apoptosis; instead, the diminished expression of CD3zeta protein is paralleled by a decrease in CD3zeta mRNA. This change in CD3zeta mRNA expression is not caused by a decrease in the transcription rate but rather by a significantly shorter CD3zeta mRNA half-life. This mechanism is sensitive to cycloheximide. Therefore, the regulation of L-Arg concentration in the microenvironment could represent an important mechanism to modulate the expression of CD3zeta and the T cell receptor and consequently of T cell function.