Differential Roles of IDO1 and IDO2 in T and B Cell Inflammatory Immune Responses.

Lauren M F Merlo,Wei-Dan Peng,James B Duhadaway,Laura Mandik-Nayak,Alexander J Muller,James D Montgomery,Peter J Murray,George C Prendergast,Andrew J Caton

doi:10.3389/fimmu.2020.01861

Abstract

Indoleamine-2,3-dioxygenase (IDO)1 and IDO2 are two closely related tryptophan catabolizing enzymes encoded by linked genes. The IDO pathway is also immunomodulatory, with IDO1 well-characterized as a mediator of tumor immune evasion. Due to its homology with IDO1, IDO2 has been proposed to have a similar immunoregulatory function. Indeed, IDO2, like IDO1, is necessary for the differentiation of regulatory T cells in vitro. However, compared to IDO1, in vivo studies demonstrated a contrasting role for IDO2, with experiments in preclinical models of autoimmune arthritis establishing a proinflammatory role for IDO2 in mediating B and T cell activation driving autoimmune disease. Given their potentially opposing roles in inflammatory responses, interpretation of results obtained using IDO1 or IDO2 single knockout mice could be complicated by the expression of the other enzyme. Here we use IDO1 and IDO2 single and double knockout (dko) mice to define the differential roles of IDO1 and IDO2 in B cell-mediated immune responses. Autoreactive T and B cell responses and severity of joint inflammation were decreased in IDO2 ko, but not IDO1 ko arthritic mice. Dko mice had a reduction in the number of autoantibody secreting cells and severity of arthritis: however, percentages of differentiated T cells and their associated cytokines were not reduced compared to IDO1 ko or wild-type mice. These data suggest that autoreactive B cell responses are mediated by IDO2, while autoreactive T cell responses are indirectly affected by IDO1 expression in the IDO2 ko mice. IDO2 also influenced antibody responses in models of influenza infection and immunization with T cell-independent type II antigens. Taken together, these studies provide evidence for the contrasting roles IDO1 and IDO2 play in immune responses, with IDO1 mediating T cell suppressive effects and IDO2 working directly in B cells as a proinflammatory mediator of B cell responses.

Highlights

Indoleamine-2,3-dioxygenase (IDO)1 and IDO2 are two closely related tryptophan catabolizing enzymes induced under inflammatory conditions that contribute to immune responses
In wt C57BL/6 mice, IDO1 mRNA is expressed at high levels in the epididymis and low levels in activated B cells (Figure 1A), whereas IDO2 is expressed at high levels in the liver and low levels in the epididymis and activated B cells (Figure 1B)
IDO1 is not expressed in the liver and neither IDO1 nor IDO2 mRNA were detectable in unstimulated B cells or unstimulated or activated T cells (Figures 1A,B)

Summary

Introduction

Indoleamine-2,3-dioxygenase (IDO) and IDO2 are two closely related tryptophan catabolizing enzymes induced under inflammatory conditions that contribute to immune responses. IDO1 is widely expressed in both immune and non-immune tissues, whereas expression of IDO2 is restricted to liver, kidney, and antigen presenting cells (dendritic cells and B cells) [1,2,3]. Both IDO1 and IDO2, along with the unrelated enzyme tryptophan dioxygenase (TDO), catalyze the first and rate-limiting step in the catabolism of tryptophan to kynurenine [4]. IDO2 has much weaker tryptophan catabolizing activity than IDO1, both as measured by enzyme activity in vitro and by analyzing levels of serum kynurenine in the absence of each enzyme in vivo [3, 5,6,7,8]. Understanding the contribution of IDO1 and IDO2 to immune responses is complicated by the fact that the genes encoding each enzyme are linked and likely arose by gene duplication [10]

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Results

Conclusion