Hypoxia, metabolism, and long-lived plasma cells (LYM6P.765)

Abstract

Abstract Evidence from multiple laboratories agrees that long-lived humoral immunity derives from long-lived plasma cells (LLPC) that reside in the bone marrow (BM), and existing literature makes a compelling case explaining that short-lived PC die due to high metabolic stress. However, the mechanism by which LLPC escape the same fate as SLPC is unexplored. We tested the hypothesis that glycolysis is used by BM LLPC, which might be triggered by hypoxic areas of the bone marrow. Hypoxyprobe™-1 (PIM) was used as an indicator of BM LLPC residing in areas of low O2 tension. PIM positive stain in PC suggests that most BM LLPC reside in hypoxic niches. In addition, data obtained from both ELISPOT and 24h ELISA suggest that Ig secretion from BM cultured in a hypoxia chamber (3% O2) is slightly enhanced in hypoxic versus normoxic conditions. Since BM PC appear to reside in hypoxic niches, we assessed whether glycolysis is the predominant metabolic strategy employed by PC. Using the MitoTracker probe that fluoresces upon oxidation in respiring mitochondria, we found BM PC in both MitoTracker-hi and -lo populations, suggesting PC may differ in their metabolic strategies, using aerobic respiration and glycolysis, respectively. BM LLPC in both Mitotracker subsets are functional as determined by ELISA and ELISPOT. Future studies will assess the role of the plasma cell “niche” in promoting and sustaining a metabolic phenotype, which likely governs long-term immunity.