Indoleamine 2,3 dioxygenase and metabolic control of immune responses

Abstract

Sustained access to nutrients is a fundamental biological need, especially for proliferating cells, and controlling nutrient supply is an ancient strategy to regulate cellular responses to stimuli. By catabolizing the essential amino acid TRP, cells expressing the enzyme indoleamine 2,3 dioxygenase (IDO) can mediate potent local effects on innate and adaptive immune responses to inflammatory insults. Here, we discuss recent progress in elucidating how IDO activity promotes local metabolic changes that impact cellular and systemic responses to inflammatory and immunological signals. These recent developments identify potential new targets for therapy in a range of clinical settings, including cancer, chronic infections, autoimmune and allergic syndromes, and transplantation.

Figure 1. Metabolic control of T cell and Treg responses via IDO

Kyn release and Trp consumption by accessory cells expressing IDO generates signals via AhR and amino-acid sensors (GCN2, mTOR), respectively, that have profound effects on T cell and Treg responses to inflammatory and antigenic signals. IDO activity in APCs also enhances Treg differentiation from naïve CD4 T cells via these metabolic pathways (not shown).

Figure 2. IDO is activated inflammation and helps create conditions that favor immune suppression and tolerance

Primary insults create local inflammation and generalized signals that activate immune cells. However, overall immune outcomes depend on the balance of additional signals that promote either effector and regulatory responses. Thus inflammation drives the immune response, but the specific character depends critically on the overall balance of immune stimulatory and regulatory pathways activated in a particular setting. Inflammatory signals that favor regulatory/suppressor outcomes often activate and/or sustain local IDO enzyme activity.