Paradoxical myeloid-derived suppressor cell reduction in the bone marrow of SIV chronically infected macaques

Abstract

Myeloid derived suppressor cells (MDSCs), which suppress anti-tumor or anti-viral immune responses, are expanded in the peripheral blood and tissues of patients/animals with cancer or viral infectious diseases. We here show that in chronic SIV infection of Indian rhesus macaques, the frequency of MDSCs in the bone marrow (BM) was paradoxically and unexpectedly decreased, but increased in peripheral blood. Reduction of BM MDSCs was found in both CD14+MDSC and Lin-CD15+MDSC subsets. The reduction of MDSCs correlated with high plasma viral loads and low CD4+ T cell counts, suggesting that depletion of BM MDSCs was associated with SIV/AIDS disease progression. Of note, in SHIVSF162P4-infected macaques, which naturally control viral replication within a few months of infection, the frequency of MDSCs in the bone marrow was unchanged. To investigate the mechanisms by which BM MDSCs were reduced during chronic SIV infection, we tested several hypotheses: depletion due to viral infection, alterations in MDSC trafficking, and/or poor MDSC replenishment. We found that the possible mobilization of MDSCs from BM to peripheral tissues and the slow self-replenishment of MDSCs in the BM, along with the viral infection-induced depletion, all contribute to the observed BM MDSC reduction. We first demonstrate MDSC SIV infection in vivo. Correlation between BM CD14+MDSC reduction and CD8+ T cell activation in tissues is consistent with decreased immune suppression by MDSCs. Thus, depletion of BM MDSCs may contribute to the pathologic immune activation during chronic SIV infection and by extension HIV infection.

MDSCs in infectious diseases: regulation, roles, and readjustment

“…In several chronic infections in which MDSC expansion limits protective immunity, depletion of MDSC reversed immunosuppression and improved disease outcome (45,48). In TB and AIDS, such interventions may in addition remove pathogen reservoirs, as MDSC can harbor these microbes (45,83). MDSC can be targeted via (i) depletion, (ii) maturation-induced ablation, (iii) interference with their pathways of genesis, and (iv) interference with their suppressive activity.…”

Bone Marrow-Derived CD4 + T Cells Are Depleted in Simian Immunodeficiency Virus-Infected Macaques and Contribute to the Size of the Replication-Competent Reservoir

“…Previous studies with nonhuman primates (NHPs) showed early BM hematopoietic defect after simian immunodeficiency virus (SIV) or simian-human immunodeficiency virus (SHIV) infection, which resulted in an impaired T cell production (20,21). A recent study looking at myeloid-derived suppressor cells (MDSC) revealed that depletion of these cells in BM could contribute to systemic immune activation and exacerbate SIV pathogenesis (22). In our paper, we focus on the CD4 ϩ T cell contribution to viral persistence; however, others have shown that other cellular subsets in the bone marrow may harbor virus as well (23).…”

Monocytic myeloid-derived suppressor cells generated from rhesus macaque bone marrow enrich for regulatory T cells

“…Increases in circulating mMDSC have been reported recently in simian immunodeficiency virus (SIV)- or influenza A-vaccinated monkeys [24, 25]. Paradoxically however, reductions in these cells have been observed in the BM of chronically SIV-infected macaques [26]. Comparison of the phenotype and function of mMDSC isolated from virally-infected monkeys and those generated in this study from normal BM cells would be of interest.…”