A novel role for indoleamine 2,3-dioxygenase (IDO) in supporting the survival of long lived plasma cells (LLPC)

Abstract

Abstract Protective antibodies against diseases such as measles and polio primarily come from bone marrow (BM) resident long lived plasma cells (LLPC) and are a key component of durable humoral immunity. As LLPC are not innately long lived a major question remains about how these cells maintain survival. Our lab has previously demonstrated that the T cell receptor, CD28, is essential for the survival and function of LLPC. Here we further demonstrate that when CD28 on LLPC ligates with CD80/CD86 on DC, it induces upregulation and activation of indoleamine 2,3-dioxygenase (IDO). IDO’s primary action is catabolizing tryptophan into kynurenine, a well-known ligand of the aryl hydrocarbon receptor (AhR). A nuclear transcription factor, AhR is known to modulate immune responses and is expressed in PC. Unexpectedly we observed that IDO KO mice have significantly less long lived antigen specific antibody titers and a decrease in LLPC specifically in the BM post immunization. Specific deletion of IDO+DC also significantly decreases LLPC in vivo. Furthermore, treatment with kynurenine in LLPC causes upregulation of CYP1A1, the downstream target of AhR. Moreover, we see an increase in CD28 expression with kynurenine treatment in murine and human PC. We propose a model where the interaction of CD28 on LLPC with CD80/CD86 on DC activates IDO, producing kynurenine, which activates AhR to further regulate CD28 expression on LLPC. These findings challenge the traditional paradigm of IDO as immunosuppressive and uncover a novel role in promoting immunity. Filling this gap in knowledge furthers our understanding of diseases that involve LLPC, but also has direct implications in future vaccine and therapeutic drug development. Support: T32 CA085183, R01CA121044