The role of Indoleamine 2,3-dioxygenase (IDO) in the survival of bone marrow resident long lived Plasma cells

Abstract

Abstract Interactions within the bone marrow microenvironment provide critical survival signals to normal resident long lived plasma cells (LLPC). Previous work in our lab has shown that CD28 is required for LLPC survival, and we know that CD28 back signaling in to CD80/86 induces IDO production from DCs within the bone marrow microenvironment. IDO is classically known to contribute to an immunosuppressive environment (specifically with respect to T cell activity) in multiple myeloma, giving these cells the ability to survive within the bone marrow. However, to our great surprise previous results demonstrate that IDO is required for durable specific antibody responses in a normal bone marrow microenvironment. Thus we hypothesize that IDO has an additional role acting as a factor to maintain the bone marrow niche for long lived plasma cell survival, and sustained antibody production. Here we show that human myeloid derived DCs co-cultured with plasma cell lines produce IDO in vitro. In vivo models were also used, including the IDO knockout mouse model to analyze their LLPCs and the bone marrow compartment. A decrease of plasma cells in the bone marrow from wild type mice compared to IDO knock out mice was observed. These findings indicate that plasma cells can interact with dendritic cells within the bone marrow to produce IDO, and that a lack of IDO leads to a decreased number of these cells. Due to IDO deficient mice being unable to maintain long term antibody production, we propose a model wherein CD28 signaling induces IDO production, which plays a role in providing a supportive niche within the bone marrow for long lived plasma cell survival and antibody production. Supported by: R01CA121044-08