Rheumatoid arthritis (RA) is a chronic and debilitating inflammatory autoimmune disease of unknown etiology. As with a variety of autoimmune disorders, evidence of elevated tryptophan catabolism has been detected in RA patients indicative of activation of the immunomodulatory enzyme IDO. However, the role that IDO plays in the disease process is not well understood. The conceptualization that IDO acts solely to suppress effector T cell activation has led to the general assumption that inhibition of IDO activity should exacerbate autoimmune disorders. Recent results in cancer models, however, suggest a more complex role for IDO as an integral component of the inflammatory microenvironment necessary for supporting tumor outgrowth. This has led us to investigate the involvement of IDO in the pathological inflammation associated with RA. Using the K/BxN murine RA model and IDO inhibitor 1-methyl-tryptophan, we found that inhibiting IDO activity had the unexpected consequence of ameliorating, rather than exacerbating arthritis symptoms. 1-Methyl tryptophan treatment led to decreased autoantibody titers, reduced levels of inflammatory cytokines, and an attenuated disease course. This alleviation of arthritis was not due to an altered T cell response, but rather resulted from a diminished autoreactive B cell response, thus demonstrating a previously unappreciated role for IDO in stimulating B cell responses. Our findings raise the question of how an immunosuppressive enzyme can paradoxically drive autoimmunity. We suggest that IDO is not simply immunosuppressive, but rather plays a more complex role in modulating inflammatory responses, in particular those that are driven by autoreactive B cells.

The orphan steroid receptor, Nur77, is thought to be a central participant in events leading to TCR-mediated clonal deletion of immature thymocytes. Interestingly, although both immature and mature murine T cell populations rapidly up-regulate Nur77 after TCR stimulation, immature CD4+CD8+ thymocytes respond by undergoing apoptosis, whereas their mature descendants respond by dividing. To understand these developmental differences in susceptibility to the proapoptotic potential of Nur77, we compared its regulation and compartmentalization and show that mature, but not immature, T cells hyperphosphorylate Nur77 in response to TCR signals. Nur77 resides in the nucleus of immature CD4+CD8+ thymocytes throughout the course of its expression and is not found in either the organellar or cytoplasmic fractions. However, hyperphosphorylation of Nur77 in mature T cells, which is mediated by both the MAPK and PI3K/Akt pathways, shifts its localization from the nucleus to the cytoplasm. The failure of immature CD4+CD8+ thymocytes to hyperphosphorylate Nur77 in response to TCR stimulation may be due in part to decreased Akt activity at this developmental stage.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects approximately 1% of the population. Although both T and B cell‐mediated autoimmune components have been implicated, the mechanism leading to the initiation of disease is not known. K/BxN mice spontaneously develop a joint inflammatory response that mimics many of the features of human RA. Importantly, in this murine model, disease induction is synchronous and predictable, allowing for the study of the factors that contribute to disease initiation and pathogenesis. In K/BxN mice, arthritis is induced by autoantibodies against the glycolytic enzyme glucose‐6‐phosphate‐isomerase (GPI). How autoreactive B and T cells escape tolerance induction to this ubiquitously expressed self‐Ag and initiate a joint‐specific autoimmune response remains unclear. Previously, our laboratory generated low affinity anti‐GPI Ig tg mice to investigate how GPI‐reactive B cells are normally tolerized by the immune system. Surprisingly, although anti‐GPI B cells show evidence of autoantigen encounter beginning in the BM, they are not tolerant to GPI. The anti‐GPI B cells remain functionally competent and can be induced to secrete autoantibodies in response to cognate T cell help both in vitro and in vivo. This suggests that they have the potential to trigger the arthritogenic autoimmune response.