Effects of the tryptophan metabolite picolinic acid on CD4+ T cells

Abstract

The tryptophan metabolite picolinic acid (PA) is one of the key metabolites, which is formed in several steps through the kynurenine pathway. The first and rate-limiting enzyme of the kynurenine pathway is indoleamine 2,3-dioxygenase (IDO). The up-regulation of IDO and subsequently the generation of tryptophan metabolites are important mechanisms of immune tolerance but also associated with various diseases, such as HIV, autoimmune diseases, neurological disorders and tumours. In this work, we could show that PA suppressed CD4+ T cell proliferation and metabolic activity in a dose-dependent manner. In contrast to other tryptophan metabolites such as kynurenine, PA had no significant effect on T cell viability. Tcell effector functions which were dependent on protein synthesis such as cytokine secretion and cell surface marker up-regulation were not or only weakly inhibited by PA. On the molecular level, we could not find any effect of PA on major signalling pathways of T-cell activation such as the MAPK, mTOR, NFAT, NFκB and AP-1 signalling pathways. In accordance with our functional observatins, T-cells exposed to PA presented with a reduced phosphorylation of c-Myc at Ser62, which is an indicator of c-Myc activation. Since this activation is mainly mediated by the MAPK ERK, it is possible that PA acts as an inhibitor of ERK activity. This hypothesis will be tested in future studies.