Tryptophan and the immune response

Abstract

SummaryThe immune system continuously modulates the balance between responsiveness to pathogens and tolerance to non-harmful antigens. The mechanisms that mediate tolerance are not well understood, but recent findings have implicated tryptophan catabolism through the kynurenine metabolic pathway as one of many mechanisms involved. The enzymes that break down tryptophan through this pathway are found in numerous cell types, including cells of the immune system. Some of these enzymes are induced by immune activation, including the rate limiting enzyme present in macrophages and dendritic cells, indoleamine 2,3-dioxygenase (IDO). It has recently been found that inhibition of IDO can result in the rejection of allogenic fetuses, suggesting that tryptophan breakdown is necessary for maintaining aspects of immune tolerance. Two theories have been proposed to explain how tryptophan catabolism facilitates tolerance. One theory posits that tryptophan breakdown suppresses T cell proliferation by dramatically reducing the supply of this critical amino acid. The other theory postulates that the downstream metabolites of tryptophan catabolism act to suppress certain immune cells, probably by pro-apoptotic mechanisms. Reconciling these disparate views is crucial to understanding immune-related tryptophan catabolism and the roles it plays in immune tolerance. In this review we examine the issue in detail, and offer additional insight provided by studies with antibodies to quinolinate, a tryptophan catabolite which is also necessary for nicotinamide adenine dinucleotide (NAD +) production. In addition to the immunomodulatory actions of tryptophan catabolites, we discuss the possible involvement of quinolinate as a means of replenishing NAD + in leucocytes, which is depleted by oxidative stress during an immune response.

Systemic application of CpG‐rich DNA suppresses adaptive T cell immunity via induction of IDO

“…We could exclude type I and type II interferons as mediators of suppression, because CpG-ODN-induced inhibition was still observed in IFNaR -/-and IFNc -/-mice. It is known that tumors and infections can induce IDO in various cells types in a IFNc-dependent manner [24,25,27]. The experiments described here failed to reveal a role for type I and II interferons in CpG-ODN-induced and IDO-mediated suppression and therefore argue for a different mode of IDO induction.…”

“…Rather, this suppression was found to be mediated by induction of IDO, an enzyme known to degrade tryptophan, an essential amino acid for proliferation of CD4 + and CD8 + T lymphocytes [26,27]. IDO can be produced by various cell types, including macrophages, immature DC, plasmacytoid DC (pDC) and non-hematopoietic cells such as trophoblasts and lung epithelial cells [25,27]. The nature of the IDOproducing cell types in the spleen is not yet clear.…”

“…The nature of the IDOproducing cell types in the spleen is not yet clear. Their identification may be complicated, because it is known that cells can express IDO in a functionally inactive form [20,25]. Preliminary experiments indicate that pDC are not involved (or solely responsible), as in vivo depletion with a pDC-specific antibody had no effect on suppression (own unpublished data).…”

“…Tumors and infections have been reported to induce IDO in an IFNc-dependent way [24,25]. Therefore we investigated whether type I and II interferons are responsible for the CpG-ODN-induced suppression described here.…”

An exploratory study of the interplay between decreased concentration of tryptophan, accumulation of kynurenines, and inflammatory arthritis

“…Catabolism of tryptophan via the kynurenine pathway is thought to play an important immunosuppressive role (1,2). In mice during an allogeneic pregnancy, inhibition of an enzyme, indoleamine 2,3 dioxygenase 1 (IDO1), which initiates catabolism of tryptophan, can evoke spontaneous abortion driven by an immunological reaction against the developing fetus (3).…”