Direct interaction with dendritic cells through CD28-CD80/CD86 supports plasma cell survival (34.9)

Abstract

Abstract The long term survival of plasma cells in their bone marrow niches, necessary to maintain persistent antibody titres, depends on specific survival signals that are produced by their interaction with bone marrow stromal cells (BMSC), interactions that remain largely uncharacterized. Both normal and malignant plasma cells (like myeloma cells) express the T-cell co-stimulatory molecule CD28 and are also known to interact with dendritic cells (DC) in bone marrow biopsies. We also know that ligating CD80/CD86 on DCs with soluble CD28/CTLA4 ligands can up-regulate IL-6, an essential plasma cell survival factor. In our studies, co-culturing CD28+ plasma cells (myeloma cell lines or primary plasma cell isolates) with immature DCs significantly up-regulated DC production of IL-6 (400 - 500 pg/ml as opposed to 40 - 70 pg/ml), which was blocked with anti-CD28 antibodies. Cell-free plasma cell-DC co-culture supernatants supported plasma cell proliferation and survival. Furthermore, plasma cell CD28 binding to CD80/CD86 on DCs induces DC expression and activity of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO), which inhibits T cell activation by depleting the essential amino acid tryptophan from the microenvironment. Our study suggests a pro-survival role for DC in regulating plasma cell survival by modulating their bone marrow micro-environment