Increased Tregs associated with elevated Indoleamine-2,3-dioxygenase activity and an imbalanced Kynurenine pathway in IFNpositive primary Sjögren's syndrome

Introduction Indoleamine-2,3-dioxygenase (IDO), the rate-limiting enzyme converting tryptophan (TRP) to kynurenine (KYN), is driven in part by type I/II IFNs. Naïve T cells are polarized into FoxP3+ regulatory T cells (Tregs) upon exposure to either IDO+ cells or KYN. Recent studies suggest the KYN pathway to reflect a crucial interface between the immune and nervous system. Here we hypothesized an increase in Tregs, in conjunction with increased IDO activity, in IFN signature positive primary Sjögren's syndrome (pSS) patients and investigated the downstream KYN pathway. Methods Serum of 71 Healthy controls (HC), 58 IFNnegative (IFNneg) and 66 IFNpositive (IFNpos) pSS patients was analyzed using HPLC, for TRP and KYN levels. CD14+ monocyte mRNA-expression of IDO and downstream enzymes in the KYN pathway were assessed using real-time quantitative PCR. CD4+CD45RO+T helper (Th) memory cell populations were analyzed by flow cytometry. Results IDO activity (KYN/TRP-ratio; p=0.0054) and percentage of CD25hiFoxP3+Tregs (p=0.039) were significantly increased in IFNpos pSS, and correlated significantly (p=0.002;r=0.509). Circulating IFNpos pSS monocytes upregulated IDO1-expression (p<0.0001), which correlated with the IFNscore (p<0.0001;r=0.816). Interestingly, the pro-apoptotic and neurotoxic downstream enzyme KMO (p=0.0057) was upregulated, whereas KATI (p=0.0003), KATIII (p=0.016) and KATIV (p=0.04) were downregulated in IFNpos pSS compared to HC. Conclusion Here we find enhanced IDO activity in conjunction with increased CD25hiFoxP3+Tregs, and identify an imbalanced KYN pathway with evidence for a shift towards potentially more pro-apoptotic and neurotoxic metabolites in IFNpos pSS patients. Intervening in these IFN and IDO-induced imbalances offers a new array of possibilities for therapeutic interventions in pSS. This article is protected by copyright. All rights reserved.

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