Microbial signatures are detected by non-clonally distributed innate receptors termed pattern recognition receptors (PRR). PRR are grouped in families and the founder toll-like receptors (TLR) have been best characterized so far. TLR are present on the plasma membrane and within endosomes and are activated by diverse microbial structures, including lipids [e.g., TLR-4 senses lipopolysaccharide (LPS)], lipoproteins (e.g., TLR-2 senses acylated peptides) and proteins (e.g., TLR-5 senses flagellin). Generally, microbial-derived cognates of TLR-2 and -4 induce M-MDSC (20, 32, 51–53). LPS, which is the major cell wall component of Gram-negative bacteria, triggers proliferation of HSC (40) and induces M-MDSC upon pulmonary instillation or subsequent infection with Salmonella spp. or Klebsiella pneumonia (35, 51). Stimulation of human monocytes with TLR-4 agonists reprograms the cells into M-MDSC in a process dependent on STAT-3 activation (54). Crosstalk between TLR/MyD88 and JAK2/STAT5 pathways following receptor activation by LPS and GM-CSF is critical for M-MDSC generation (35, 51). The adaptor MyD88, which converges signals from multiple TLR, has also been implicated in generation of MDSC during polymicrobial sepsis (55). TLR-4 appears dispensable for sepsis-induced suppression of T cells (55) thereby indicating that IL-1, which binds IL-1R upstream of MyD88, conditions MDSC differentiation.

Several bacterial and viral agonists of TLR-2 promote M-MDSC differentiation from monocytes and in certain instances precise signaling pathways have been identified. S. aureus lipopeptides activate TLR2/6 dimers in skin cells for IL-6 production which in turn promote local MDSC accumulation (32). HCV reprograms monocytes into M-MDSC by stimulating TLR-2. More precisely, HCV core proteins or HCV cell culture-derived virions trigger TLR-2/PI3K/AKT/STAT3 pathway and this leads to cytokine production, notably IL-10 and TNF-α, and monocyte differentiation into MDSC (19–21). By contrast, TLR-3 ligation restricts HCV and LPS-induced M-MDSC differentiation (19, 52). Nonetheless, vesicular stomatitis virus activation of TLR-3 induces MDSC expansion (56). Alike TLR-3, TLR-7 activation by influenza virus blocks MDSC, including M-MDSC, accumulation in infected lungs (44). Both TLR-3 and -7 are located in endosomes. Whether signal compartmentalization, notably at the cell membrane or within endosomes, is critical for MDSC genesis remains to be established. Very little information exists on the roles of cytosolic PRR, such as nod-like receptors and AIM-like receptors, in monocyte reprogramming or M-MDSC generation. Moreover, many pathogens, notably mycobacteria, simultaneously stimulate multiple PRR (57) and the net outcome of such innate recognition on M-MDSC in TB awaits clarification.

Host alarmins that activate PRR have also been implicated in MDSC generation. S100A proteins, high-mobility-group-protein B1 and heat-shock proteins bind the receptor for advanced glycation products (RAGE), TLR-2, and TLR-4. In cancer and autoimmune diseases, these ligands have been associated with increased dynamics of MDSC, including M-MDSC (58–60). Just like microbial-derived PRR agonists, alarmins may induce cytokine release, such as IL-6 and subsequent autocrine or paracrine differentiation of immature mononuclear cells toward MDSC (61). In chronic infections, for instance, in TB patients, S100A8/9 proteins are abundant in the lung (62). These alarmins besides driving recruitment of MDSC (63) bind RAGE and subsequently upregulate ARG1, a key suppressive enzyme in M-MDSC (2). Since tissue damage often occurs during microbial insult, PRR stimulation by host-derived danger molecules along with microbial-derived agonists could contribute to the regulation of MRC. Similarly, synergy between microbial products, such as LPS, and inflammatory cytokines, notably IFN-γ, restricts differentiation of DCs and fosters genesis of M-MDSC in the bone marrow (64).

For many microbes, the precise pathways required for M-MDSC genesis are not known. Mycobacteria induce accumulation of such cells irrespective of key virulence features, notably the type VII secretion system. M-MDSC have been reported for both M. tuberculosis and the vaccine BCG (29, 30, 50, 65). Mycobacterial glycolipids appear sufficient to induce these regulatory monocytes, as indicated by the presence of MDSC in animals inoculated with complete Freund’s adjuvant (66). In contrast to mycobacteria, non-colitogenic bacteria and oncogenic gut species (Fusobacterium nucleatum, pks⁺ Escherichia coli) do not trigger M-MDSC, whereas enterotoxigenic Bacillus fragilis employs the toxin to prime epithelial cells for IL-17 and M-MDSC expansion (34). HIV and SIV infection triggers accumulation of M-MDSC in the blood and their reduction in the bone marrow, which correlates with plasma viral loads and disease progression (25, 49). Several HIV viral factors promote expansion of the M-MDSC or reprogramming of monocytes. Human monocytes stimulated with HIV gp120 (23, 24) and/or with Tat proteins (54) acquire T-cell suppressive activity. This differentiation requires autocrine release of IL-6 and activation of STAT-3 (23, 54). HBV surface antigen similarly triggers differentiation of human monocytes toward M-MDSC in an autocrine manner depending on activation of the kinase ERK and the transcription factor STAT-3 (18). The necessity of specific kinases, such as ERK (18) and AKT (19, 20) for microbial-induced M-MDSC generation resembles kinase signatures of MDSC in cancer (67). Similarly, STAT-3 is required for M-MDSC in cancer (68) as well as during infection with HIV (23, 54), HCV (20, 22), and stimulation with bacterial LPS (54). For many bacterial (Mycobacterium spp., F. tularensis, Porphyromonas gingivalis) (29, 30, 42, 50, 69) and viral pathogens [vaccinia virus, lymphocoriomeningitis virus (LCMV), MCMV, murine gamma virus, LP-BM5] (70–72), and protozoa (Leishmania spp.)(73, 74), the host pathways or microbial signatures required for M-MDSC genesis are still undefined.

Immunosuppression by MDSC has the potential to inhibit innate and adaptive immune cell activation, proliferation, viability, trafficking, and cytokine production. M-MDSC utilize a variety of suppressive mechanisms and likely differ in their ability to initiate antigen-specific versus non-specific suppression (126, 127). Each immune suppressive function is determined by the type of MRC, the microenvironmental components and the state of T-cell activation, favoring the probability that non-specific and antigen-specific suppressive mechanisms may coincide. Although not the focus of this review, as an example, PMN-MDSC can present peptides to T cells, but their low expression of major histocompatibility complex (MHC) II and costimulatory molecules, suggest they might only affect CD8 T-cell responses in an antigen-specific manner, as reported during retrovirus infection (128). This idea is supported by reports on MDSC-mediated inhibition of antigen-specific CD8 T-cell responses in tumors, likely due to the MHC I-restricted nature of cancer MDSC (2, 127, 129, 130). In infection, antigen-specific immunosuppression of CD8 T cells by M-MDSC is restricted to polymicrobial sepsis (131), HCV (21), HBV (46), murine encephalomyelitis virus (132), SIV and HIV infections (26), and LCMV infection (71). Data on the effect of MDSC on CD4 T helper cell (TH) subsets during infectious diseases are limited, but do exist as a result of the MHC-independent suppressive effects of MDSC in the context of HCV (21), HIV (24), and murine encephalomyelitis virus infection (132). During BCG-induced pleurisy, transmembrane TNF on M-MDSC restricts proliferation of CD4 T cells via interaction with lymphocyte-expressed TNFR2 (80). Results on MDSC interaction with TH17 and TH2 polarized CD4 T cells are contradictory and reports exist of mainly PMN-MDSC-mediated induction and suppression of TH17 responses in cancer, autoimmunity and infection (133–138), likely indicating that the combination of mediators present in the microenvironment determines the final outcome. In turn, TH1 and TH2 are involved in the expansion and activation of MDSC in cancer and also hepatitis (137, 139). Interestingly, recent findings suggest that CD1d-restricted natural killer T cells can convert immunosuppressive murine-MDSC into immune stimulating APCs following influenza virus infection, via their interaction with CD40 (140).

Regulatory T cells (Treg) are equally important components of the host immunoregulatory network. Data suggest reciprocal regulation of MDSC and Treg through mechanisms involving presence of IL-10, TGF-β, IL-4Rα, p47phox, PD-L1, TGF-β, and CD40–CD40L interactions, ARG1 induction and CCR-5-mediated recruitment (91, 126, 141–144). Interactions between total MDSC and Treg in cancer are well described (145, 146) with Treg depletion reducing MDSC immunosuppression by lowering their expression of PD-L1 and IL-10 production (147). Evidence of interaction in non-cancerous models, including type-1 diabetes, cardiac allograft and airway hyper-responsiveness, also exist (148–150). More specifically, the induction of Treg by M-MDSC, has also been described during HIV infection and shown to contribute to host immunosuppression (23, 49, 54). Data by O’Connor suggest reciprocal crosstalk between M-MDSC and Treg during LP-BM5-induced murine AIDS. Here, M-MDSC subsets display differential suppression of T- and B-cells, thereby indicating functionally overlapping, but distinguishable, immunosuppressive effects (27, 95). Incubation of M-MDSC from peripheral blood of HIV-1-infected individuals, even those on antiretroviral therapy with undetectable viremia, with CD4 T cells from healthy individuals, significantly increased differentiation of Foxp3 Treg, whereas depletion of MDSC significantly increased IFN-γ production by CD4 T cells (54).

Information on MDSC interaction with B-cells only recently started to accumulate. In autoimmune disease, M-MDSC inhibit B-cell proliferation and antibody production via an iNOS and a PGE2-induced pathway (151). However, opposing data demonstrated that the total MDSC population promotes proliferation and differentiation of immunoglobulin-A-producing immunosuppressive plasma B-cells via cell contact in mouse tumor models (152). In infectious diseases, M-MDSC suppressed B-cell responsiveness to retroviral infection in mice via iNOS and the negative immune checkpoint regulator V-domain Ig Suppressor of T-cell Activation (VISTA) (72, 93).

Data on MDSC interaction with myeloid cells, such as DC, neutrophils, and macrophages in infectious diseases, are equally restricted, with reports mainly revealing that their inhibitory effects are exacerbated by cross-regulation with macrophages at tumor sites. In lung infections, such as Pneumocystis pneumonia (PcP), M-MDSC expressing PD-L1 are induced and impair alveolar macrophage (AM) phagocytic activity while increasing AM expression of PD-1 (153). MDSC interaction with neutrophils has been described in mice infected with K. pneumoniae or challenged with LPS, demonstrating that MDSC efferocytose infected, apoptotic neutrophils (35). Furthermore, M-MDSC suppress DC maturation, antigen uptake, migration, and TH1 cytokine production following administration of a DC vaccine for malignant melanoma (154). Similar findings were reported following LPS stimulation and in hepatocellular carcinoma, where both MDSC subsets reduced expression ofMHC II, stimulatory molecules on DC, and cytokine production (64, 155). It stands to reason that these MDSC-induced modifications, affecting DC-mediated activation of T cells and antigen uptake, could also be effective in infectious diseases and warrant further investigation.

Reports on MDSC-mediated impairment of NK cell function emanate mainly from the cancer field. NK cells are critical to the innate immune system, exhibit cytotoxic and cytolytic functions, and target pathogens and malignant cells. In tumors, M-MDSC and also a population containing M-MDSC, inhibit cytotoxic activity and cytokine production by NK cells through cell contact-dependent mechanisms involving membrane-bound TGF-β and NKp30 ligand (156–158). NK cell-mediated suppression by total HLA-DR^loCD33⁺CD11b^lo MDSC has also been reported in chronic HCV infection and it is mediated via an ARG1-dependent inhibition of mammalian target of rapamycin (102).

Viral infections are known for their induction of pro-inflammatory mediators associated with the generation of MDSC. E.g., M-MDSC are increased in both clinical and experimental viral infections, such as HIV, SIV, and LP-BM5 (25–27, 49, 93, 94). During these retroviral infections, increased levels of M-MDSC are likely detrimental to disease outcome and facilitate pathogen survival, when considering the TH1 immunosuppressive effect and correlation to viral load and CD4 T-cell count (24, 49, 54, 95). Interestingly, HIV infection-mediated expansion of M-MDSC in peripheral blood mononuclear cells may also negatively affect containment of other concurrent infections, as reported for cytomegalovirus (CMV) infection (96). Recruitment of M-MDSC-like cells were also reported for murine CMV mono-infection and shown to impair viral clearance (70). Information on MDSC in HCV infections has been variable, but largely provides evidence of unfavorable effects on host protective immunity (19, 22, 104). Increased MDSC frequencies positively correlate with HCV viral load and decreased CD8 T-cell function (21, 99). Reports show that elevated levels of immature Lin⁻HLA-DR⁻CD33⁺CD11b⁺ MDSC, consisting of M-MDSC and PMN-MDSC, in chronic HCV-infected patients, decline following successful IFN-α treatment (98), while treatment-naive HCV-infected individuals show significantly increased liver- and circulating MDSC frequencies compared to treated and uninfected individuals (99, 161). Nonetheless, other in vivo investigations failed to show significant MDSC elevations or an association with viral load (100). Ning et al. also provided evidence of increased M-MDSC in HCV-infected patients; however, this was correlated with age and not viral load, suggesting that the immune response caused by viral replication, rather than the virus itself, is responsible for increased M-MDSC (101). HBV infections are also associated with induction of MDSC. HLA-DR^−/lowCD14⁺ M-MDSC occur at higher frequency in peripheral blood of chronic HBV-infected patients and suppress HBV-specific CD8 T-cell cytotoxicity (105). Suppressive MDSC are also increased in murine HBV infection (45) and drive CD8 T-cell exhaustion via their crosstalk with γδT-cells (46). M-MDSC accumulate during viral coinfections, but frequencies appear to be similar with those observed in mono-infections (103). E.g., elevated number of MDSC were reported for HCV/HIV (103) and shown to regulate excessive IFN-γ production in HIV/CMV coinfected individuals (96).

Bacterial infections are often associated with excessive inflammation or low-grade chronic production of pro-inflammatory cytokines and chemokines known to induce the expansion and activation of MDSC. E.g., chronic S. aureus infection in mice is sustained by M-MDSC and PMN-MDSC expressing ARG1, iNOS, and IL-10 which foster an immunosuppressive environment and impair monocyte/macrophage responsiveness (33, 47, 48, 108). Similarly, during infections with intracellular bacteria, such as F. tularensis, MDSC frequencies correlate with the extent of tissue pathology, loss of pulmonary function, and host mortality (42). Several reports demonstrate that inoculation of mice with BCG or infection with M. tuberculosis induce M-MDSC that diminish pathogen control and promote disease lethality (50, 65, 109). Obregón-Henao provided new evidence, demonstrating accumulation of ARG1-producing MDSC in M. tuberculosis-infected mice (41). Similar findings were reported in human TB, with increased immunosuppressive M-MDSC in TB patients and individuals with recent exposure to TB patients (28, 110). More recently, a protective role of M-MDSC in early stages of BCG-induced pleurisy was reported (80). This effect has been linked to TNF-dependent suppression of CD4+ T-cell inflammation. MDSC were also highly induced following infection with a clinical isolate of multidrug-resistant K. pneumoniae. These M-MDSC express anti-inflammatory surface markers and displayed compromised phagocytic abilities (3). Impairment of IL-10 production from total MDSC inhibited resolution of K. pneumoniae-induced inflammation (4). H. pylori-mediated inflammation of the gastric mucosa also promoted an influx of M-MDSC that countered host protective TH1 immune responses (111). In addition, MDSC gradually increase after polymicrobial sepsis (75–77), with M-MDSC mainly promoting sepsis-induced mortality early during infection (75).

TH17-polarized immunity is generally required for protection against fungal infections; however, fungi modulate host immunity by inducing immunosuppressive MDSC which could also benefit the host by reducing hyperinflammatory responses (84). The majority of studies only report the induction of PMN-MDSC following infection with pathogenic fungi, such as Candida albicans and Aspergillus fumigatus (84, 162). In line with this, treatment of mice with yeast-derived antigens, such as β-glucan specific to dectin-1, reduced accumulation of PMN-MDSC but not M-MDSC and significantly decreased tumor burden (163).

Induction of potent TH1 immunity is generally sufficient to protect the host against debilitating protozoal expansion and pathology. While MDSC are typically detrimental to diseases requiring a robust host protective TH1 response, MDSC induction could in fact be beneficial during infections triggering inflammation-mediated tissue damage. For example, chronic and acute protozoan infections with L. major or Trypanosoma cruzi, mediate induction of M-MDSC which protect against pathology and parasite load, despite suppression of T-cell proliferation (73, 116, 118), although contradictory evidence have been reported (117). Similar results were shown in a mouse model of Toxoplasma gondii infection, where the total MDSC population induced hyporesponsiveness and were required for resistance against the pathogen (119). Corroborating work demonstrated that the absence of cells resembling total MDSC during acute T. gondii infection resulted in extensive intestinal necrosis due to the host TH1 inflammatory response (119, 120). More recent data on L. donovani provided evidence of the expansion of myeloid cells, likely a combination of M-MDSC and PMN-MDSC, in the spleens of infected BALB/c and C57BL/6 mice. These cells exhibit TH1 immunosuppressive features and their immunosuppressive capacity is reduced following soluble leishmanial antigen vaccination (114, 115).

Helminths characteristically cause stable, long-term infections with severe host immunomodulatory consequences, such as triggering TH2 host immune polarization. Several helminth species and their excretory/secretory products induce accumulation of M-MDSC, including Schistosoma spp. (121), Echinnococcus granulosus (122), and Nippostrongylus brasiliensis (123). Important work in a mouse model of Heligmosomoides polygyrus bakeri infection revealed the induction of a MDSC subset, likely comprising M-MDSC and PMN-MDSC, with TH2 immunosuppressive capabilities that exacerbate infection and worm burden (124, 125). Another important consideration during helminth infections is the host protective effect of MDSC-mediated suppression of TH1 immunity and induction of TH2 immunity. E.g., MDSC mediate enhanced pathogen clearance in a model of N. brasiliensis infection, although this appears to be specific to the granulocytic subset and might increase host susceptibility to diseases requiring TH1 for protection (123).

Monocytic myeloid-derived suppressor cells have been investigated only in a number of infections. In some circumstances, this MRC subset emerges as a regulator of disease pathogenesis. Based on depletion studies in animal models and correlative studies in humans undergoing anti-infective therapy, M-MDSC have both host-destructive and -protective roles. They promote establishment and progression of HIV/SIV (24, 25, 49), LCMV (71), staphylococcal prosthetic complications (33, 48, 108), and TB (29, 30) (Table 1). On the contrary, several studies indicate that this MRC subset protects from immunopathology, particularly in certain acute bacterial infections (35) and in protozoal infection (73), but also at distinct stages of viral infection with vaccinia virus (164). In such circumstances, M-MDSC contribute to resolution of inflammation or prevent disease flares. Such dual roles may correlate with biology of M-MDSC, notably their interaction with pathogens.