LP-BM5 Retrovirus-Expanded Monocytic Myeloid-Derived Suppressor Cells Alter B Cell Phenotype and Function.

Our laboratory demonstrated that infection with the murine retrovirus LP-BM5 results in increased numbers of monocytic myeloid-derived suppressor cells (M-MDSCs) and that these M-MDSCs suppress not only T but also B cell responses. Because of the paucity of studies regarding the effects of MDSCs in general on B cells, we focused on these understudied B cell targets for M-MDSC effects on B cell phenotypic and functional parameters. M-MDSCs specifically decreased the proliferation of transitional type 2 (T2) B cells in response to polyclonal stimulation but increased germinal center and Ab-secreting B cell proportions and class-switched Ig production. Additionally, M-MDSCs inhibited the expression of CD40 and MHC class II on stimulated B cells and suppressed Ag presentation to Ag-specific CD4+ T cells. These alterations of the B cell compartment coincided with decreases in aerobic glycolysis, mitochondrial respiration, and glucose consumption; the latter specifically decreased in the T2 subset. To compare B cell targets of ex vivo M-MDSC suppression with the status of B cells during the course of LP-BM5-induced pathogenesis, including immunodeficiency in vivo, B cells from LP-BM5-infected mice were collected and analyzed. LP-BM5 infection resulted in several analogous alterations of B cells, as were observed with retrovirally expanded M-MDSC suppression in vitro, including decreased proliferation of T2 B cells, an increased proportion of germinal center and Ab-secreting B cells, increased production of class-switched Abs, decreased expression of CD40, and decreased metabolic activity upon stimulation.

The Role of Myeloid-Derived Suppressor Cells in Viral Infection.

Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells that are well described as potent immune regulatory cells during human cancer and murine tumor models. Reports of MDSCs during viral infections remain limited, and their association with immunomodulation of viral diseases is still being defined. Here, we provide an overview of MDSCs or MDSC-like cells identified during viral infections, including murine viral models and human viral diseases. Understanding the similarities and/or differences of virally induced versus tumor-derived MDSCs will be important for designing future immunotherapeutic approaches.

Myeloid-derived suppressor cells in murine AIDS inhibit B-cell responses in part via soluble mediators including reactive oxygen and nitrogen species, and TGF-ß.

Monocytic myeloid-derived suppressor cells (M-MDSCs) were increased during LP-BM5 retroviral infection, and were capable of suppressing not only T-cell, but also B-cell responses. In addition to previously demonstrating iNOS- and VISTA-dependent M-MDSC mechanisms, in this paper, we detail how M-MDSCs utilized soluble mediators, including the reactive oxygen and nitrogen species superoxide, peroxynitrite, and nitric oxide, and TGF-ß, to suppress B cells in a predominantly contact-independent manner. Suppression was independent of cysteine-depletion and hydrogen peroxide production. When two major mechanisms of suppression (iNOS and VISTA) were eliminated in double knockout mice, M-MDSCs from LP-BM5-infected mice were able to compensate using other, soluble mechanisms in order to maintain suppression of B cells. The IL-10 producing regulatory B-cell compartment was among the targets of M-MDSC-mediated suppression.