CD28 mediated survival in plasma cells involves redox regulator thioredoxin (TUM7P.954)

Abstract

Abstract Very little is known about the molecules that mediate essential prosurvival interactions between plasma cells (PC) and bone marrow stroma. We have shown that both normal and transformed plasma cells (myeloma, MM) express CD28 (prototypic T cell costimulatory molecule) that correlates with increased survival in MM. We had previously shown that CD28 activation directly with agonistic antibodies or indirectly with CD80/CD86+ (CD28 ligands) dendritic cells protect MM cells against cell death. MM-CD28 also interacts with other CD86+ MM cells to maintain enhanced survival that can be reversed with CD86 blockers like CTLA4Ig. Additionally, we also show that CD28 activation is essential to help plasma cells overcome intrinsic redox stress, a result of increased protein synthesis and metabolic activity (Bertolotti et al., 2010) which if not regulated can lead to cell death. For the first time, we show that CD28 activation not only drives survival via increased NFκB activity, but it also decreases ROS levels via the redox regulator thioredoxin (TRX-1), inhibition of which increased ROS, decreased TRX-1 expression and NFκB activity and reversed CD28 mediated survival in MM. Also, TRX-1 inhibition enhanced CTLA4Ig’s anti-survival effect on MM. Interestingly, gene expression datasets of long lived plasma cells from patients correlate with TRX-1 expression with increased survival, highlighting the vital role this redox regulator plays in PC survival.