Myeloid-derived suppressor cells: paradoxical roles in infection and immunity

Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature suppressor cells that are generated due to aberrant myelopoiesis under pathological conditions. Although MDSCs have been recognized for more than 20 years under the guise of different monikers, these particular populations of myeloid cells gained more attention recently due to their immunosuppressive properties, which halt host immune responses to growing cancers or overwhelming infections. While MDSCs may contribute to immune homeostasis after infection or tissue injury by limiting excessive inflammatory processes, their expansion may be at the expense of pathogen elimination and thus may lead to disease persistence. Therefore, MDSCs may be either damaging or obliging to the host by attenuating, for example, antitumor or anti-infectious immune responses. In this review, we recapitulate the biological and immunological aspects of MDSCs, including their generation, distribution, trafficking and the factors involved in their activation, expansion, suppressive functions, and interplay between MDSCs and regulatory T cells, with a focus on the perspectives of infection and inflammation.

Fig. 1

The genesis of MDSCs. Long-term multipotential hematopoietic stem cells in the bone marrow give rise to short-term hematopoietic stem cells, which further differentiate into multipotent myeloid progenitors and then common myeloid progenitors. These evolve into IMCs, which under steady-state conditions leave the bone marrow as myeloid precursor cells and migrate to peripheral tissues, such as the spleen and lymph nodes, where they differentiate into macrophages, DCs and granulocytes/neutrophils under the influence of specific tissue factors. Under pathological conditions, such as progressive infection/inflammation or growing tumor burden, these IMCs follow a different differentiation pathway to produce MDSCs with suppressive functions. Notably, resolution of infection or tumor permits MDSC development toward the steady-state myeloid development process.

Fig. 2

Paradoxical roles for MDSCs in early and late phases of infection. Early infection is characterized by the emergence of MDSCs which appear to be involved in innate host responses to infectious pathogens, with expression of proinflammatory mediators and cytokines and the general appearance of a more M1-like phenotype. These cytokines include IL-6, IL-12, and TNFα, amongst others, and several of these factors may contribute to further MDSC expansion. Chronic or late infection is characterized by the emergence of an M2-like phenotype, with blast-like nuclei and the expression of significant ARG1 and iNOS as well as cytokines such as IL-10 and TGF-β. The milieu generated contributes to an immunosuppressive/anti-inflammatory environment that includes blunted CD4 and CD8 T cell responses and expansion of both natural (nT_reg) and induced T_reg (iT_reg) cells. MIP1α = Macrophage-inflammatory protein 1α.