IMMUNOBIOLOGY 2-Microglobulin as a negative regulator of the immune system: high concentrations of the protein inhibit in vitro generation of functional dendritic cells

Two common features in human immunodeficiency virus infection and acquired immunodeficiency syndrome, rheumatoid arthritis, and hematologic malignancies including multiple myeloma are elevated serum levels of 2microglobulin ( 2M) and activation or inhibition of the immune system. We hypothesized that 2M at high concentrations may have a negative impact on the immune system. In this study, we examined the effects of 2M on monocyte-derived dendritic cells (MoDCs). The addition of 2M (more than 10 g/mL) to the cultures reduced cell yield, inhibited the up-regulation of surface expression of human histocompatibility leukocyte antigen (HLA)–ABC, CD1a, and CD80, diminished their ability to activate T cells, and compromised generation of the type-1 T-cell response induced in allogeneic mixed-lymphocyte reaction. Compared with control MoDCs, 2M-treated cells produced more interleukin-6 (IL-6), IL-8, and IL-10. 2M-treated cells expressed significantly fewer surface CD83, HLA-ABC, costimulatory molecules, and adhesion molecules and were less potent at stimulating allospecific T cells after an additional 48-hour culture in the presence of tumor necrosis factorand IL-1 . During cell culture, 2M down-regulated the expression of phosphorylated mitogenactivated protein (MAP) kinases, extracellular signal-related kinase (ERK), and mitogen-induced extracellular kinase (MEK), inhibited nuclear factorB (NFB), and activated signal transducer and activator of transcription-3 (STAT3) in treated cells, all of which are involved in cell differentiation and proliferation. Thus, our study demonstrates that 2M at high concentrations retards the generation of MoDCs, which may involve down-regulation of major histocompatibility complex class I molecules, inactivation of Raf/MEK/ERK cascade and NFB, and activation of STAT3, and it merits further study to elucidate the underlying mechanisms. (Blood. 2003;101: 4005-4012)