Human Primary CD4 + T Cells Activated in the Presence of IFN- α 2b Express Functional Indoleamine 2,3-Dioxygenase

Abstract

Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme in the catabolism of tryptophan. By creating a local microenvironment in which levels of tryptophan are low, IDO-expressing antigen-presenting cells (APC) could regulate T cell activation. This may be relevant to control both viral and bacterial replication as well as neoplastic cell growth. Interferon-α (IFN-α) is an antiviral cytokine affecting cellular differentiation. In addition, it reduces proliferation of CD4⁺ T cells by several molecular mechanisms. To dissect the molecular steps responsible for the INF-mediated antiproliferative activity, we sought to determine whether activated primary CD4⁺ T cells in the presence of IFN-α would produce IDO. We demonstrate here that IDO mRNA is not present in resting CD4⁺ T cells. Stimulation with anti-CD3 plus interleukin-2 (IL-2) induces expression of IDO mRNA (about 2000 copies/150,000 cells), as determined by semiquantitative RT-PCR. When cells were stimulated in the presence of IFN-α, expression of IDO mRNA was significantly increased (more than 12,000 copies/150,000 cells). Functional analysis of IDO activity paralleled the results obtained with RT-PCR, demonstrating increased production of active enzyme in CD4⁺ T cells stimulated in the presence of IFN-α. Our results indicate that IFN-α modulates levels of IDO produced by activated CD4⁺ T cells. This would likely affect bystander cells by modifying levels of tryptophan in the local microenvironment.