Rheumatoid arthritis (RA) and other autoimmune disorders are associated with altered activity of the immunomodulatory enzyme indoleamine-2,3-dioxygenase (IDO). However, the precise contributions of IDO function to autoimmunity remain unclear. Here, we examine the effect of two different IDO enzymes, IDO1 and IDO2, on the development of autoimmune arthritis in the KRN preclinical model of RA. We find that IDO2, not IDO1, is critical for arthritis development, providing the first direct evidence of separate in vivo functions for IDO1 and IDO2. Mice null for Ido2 display decreased joint inflammation relative to wild-type mice due to a reduction in pathogenic autoantibodies and antibody secreting cells. Notably, IDO2 appears to specifically mediate autoreactive, but not normal B cell responses, as total serum Ig levels are not altered and IDO2 ko mice are able to mount productive antibody responses to model antigens in vitro and in vivo. Reciprocal adoptive transfer studies confirm that autoantibody production and arthritis are modulated by IDO2 expression in a cell type extrinsic to the T cell. Taken together, our results provide the first insights into IDO2 function by defining its pathogenic contributions to autoantibody-mediated autoimmunity.

Mechanistic insight into how adaptive immune responses are modified along the self-nonself continuum may offer more effective opportunities to treat autoimmune disease, cancer and other sterile inflammatory disorders. Recent genetic studies in the KRN mouse model of rheumatoid arthritis demonstrate that the immunomodulatory molecule IDO2 modifies responses to self antigens, however, the mechanisms involved are obscure. In this study, we show that IDO2 exerts a critical function in B cells to support the generation of autoimmunity. In experiments with IDO2-deficient mice, adoptive transplant experiments demonstrated that IDO2 expression in B cells was both necessary and sufficient to support robust arthritis development. IDO2 function in B cells was contingent on a cognate, antigen-specific interaction to exert its immunomodulatory effects on arthritis development. We confirmed a similar requirement in an established model of contact hypersensitivity, where IDO2-expresing B cells are required for a robust inflammatory response. Mechanistic investigations showed that IDO2 deficient B cells lacked the ability to upregulate the co-stimulatory marker CD40, suggesting IDO2 acts at the T:B cell interface to modulate the potency of T cell help needed to promote autoantibody production. Overall, our findings revealed that IDO2 expression by B cells modulates autoimmune responses by supporting the cross-talk between autoreactive T and B cells.

Rheumatoid arthritis (RA) is a debilitating inflammatory autoimmune disease with no known cure. Recently, we identified the immunomodulatory enzyme indoleamine-2,3-dioxygenase 2 (IDO2) as an essential mediator of autoreactive B and T cell responses driving RA. However, therapeutically targeting IDO2 has been challenging given the lack of small molecules that specifically inhibit IDO2 without also affecting the closely related IDO1. In this study, we develop a novel monoclonal antibody (mAb)-based approach to therapeutically target IDO2. Treatment with IDO2-specific mAb alleviated arthritis in two independent preclinical arthritis models, reducing autoreactive T and B cell activation and recapitulating the strong anti-arthritic effect of genetic IDO2 deficiency. Mechanistic investigations identified FcγRIIb as necessary for mAb internalization, allowing targeting of an intracellular antigen traditionally considered inaccessible to mAb therapy. Taken together, our results offer preclinical proof of concept for antibody-mediated targeting of IDO2 as a new therapeutic strategy to treat RA and other autoantibody-mediated diseases.

Several autoimmune disorders, including rheumatoid arthritis (RA), are associated with altered activity of the immunomodulatory enzyme indoleamine-2,3-dioxygenase (IDO). However, the precise contributions of IDO function to autoimmunity remain unclear. We examined the effect of two different IDO enzymes, IDO1 and IDO2, on the development of autoimmune arthritis in the KRN preclinical model of autoimmune arthritis by comparing the effects of both genetic knockout models and chemical inhibitors of IDO on joint inflammation. We find that IDO2, but not IDO1, is critical for arthritis development, providing the first direct evidence of separate in vivo functions for IDO1 and IDO2. Specifically, IDO2 knockout mice display decreased joint inflammation relative to wild-type mice due to a reduction in pathogenic autoantibodies and antibody secreting cells. Notably, IDO2 appears to specifically mediate autoreactive, but not normal B cell responses, as total serum Ig levels are not altered and IDO2 ko mice are able to mount productive antibody responses to model antigens in vitro and in vivo. Reciprocal adoptive transfer studies confirmed that autoantibody production and arthritis are modulated by IDO2 expression in a cell type extrinsic to the T cell. Future work will define the relevant cell types for IDO2 activity. Our results provide the first insights into the previously unknown function of IDO2 by defining its pathogenic contributions to autoantibody-mediated autoimmunity.

The tryptophan catabolizing enzymes indoleamine 2,3-dioxygenase (IDO) 1 and 2 lie at the interface between metabolism and immunity. Recently, we identified a unique functional role for IDO2 in modulating the initiation and severity of autoimmune arthritis in a murine model of disease. We find that IDO2, but not its better-studied counterpart IDO1, acts as a pro-inflammatory mediator affecting autoantibody production and T helper cell function in the KRN preclinical model of arthritis. Reciprocal adoptive transfer experiments demonstrate that IDO2 acts by a B-cell intrinsic mechanism to regulate inflammation. IDO2 function in B cells was contingent on a cognate, antigen-specific interaction to exert its immunomodulatory effects on arthritis development. Alterations in costimulatory molecules and associated cytokines involved in cross-talk between B and T cells suggest that IDO2 acts at the T:B cell interface to modulate the potency of T cell help needed to promote autoantibody production. Given the paucity of novel therapies for rheumatoid arthritis and related autoimmune disorders, IDO2 should be considered as a potential novel therapeutic target for modulating disease pathways leading to autoimmunity. However, therapeutically targeting IDO2 has been challenging due to the lack of small molecules that specifically inhibit IDO2 without also affecting the closely related IDO1. To this end, we have recently begun development and characterization of approaches that ameliorate disease by specifically targeting IDO2. We find that we are able to recapitulate the reduction in arthritis seen in genetic knockouts with IDO2-targeted therapies in preclinical models of disease.