- Research Article
- Open Access
A Paradoxical Role for Myeloid-Derived Suppressor Cells in Sepsis and Trauma
© The Feinstein Institute for Medical Research 2011
- Received: 15 September 2010
- Accepted: 12 November 2010
- Published: 12 November 2010
Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of immature myeloid cells whose numbers dramatically increase in chronic and acute inflammatory diseases, including cancer, autoimmune disease, trauma, burns and sepsis. Studied originally in cancer, these cells are potently immunosuppressive, particularly in their ability to suppress antigen-specific CD8+ and CD4+ T-cell activation through multiple mechanisms, including depletion of extracellular arginine, nitrosylation of regulatory proteins, and secretion of interleukin 10, prostaglandins and other immunosuppressive mediators. However, additional properties of these cells, including increased reactive oxygen species and inflammatory cytokine production, as well as their universal expansion in nearly all inflammatory conditions, suggest that MDSCs may be more of a normal component of the inflammatory response (“emergency myelopoiesis”) than simply a pathological response to a growing tumor. Recent evocative data even suggest that the expansion of MDSCs in acute inflammatory processes, such as burns and sepsis, plays a beneficial role in the host by increasing immune surveillance and innate immune responses. Although clinical efforts are currently underway to suppress MDSC numbers and function in cancer to improve antineoplastic responses, such approaches may not be desirable or beneficial in other clinical conditions in which immune surveillance and antimicrobial activities are required.
Over the last decade, a novel heterogeneous population of immature myeloid cells with immunosuppressive properties has been described, and these cells have recently been coined myeloid-derived suppressor cells (MDSCs) (1–3). Much of the early work on the origins and functions of these cells has been in experimental and human cancer, in which these populations are known to be immunosuppressive and to result in both reduced immune surveillance and antitumor cytotoxicity (2). However, more recent findings suggest that expansion of these immature myeloid cell populations may not be limited to cancer, and that they are linked to most if not all chronic and acute inflammatory processes (3). Therefore, should MDSCs be viewed solely from the context of an anomalous and pathologic response to cancer or could the expansion of these cell populations be considered an integral component of the host response to any inflammatory stimuli? Rather than an adverse immunosuppressive response, the expansion of this cell population(s) more than likely represents a complex balance between increased immune surveillance and dampened adaptive immune responses common to many inflammatory responses.
In this review we explore the origins of these cell populations during inflammation, focusing on their role in acute inflammatory processes such those that occur during trauma and sepsis. We propose that the overall role of MDSCs involves much more than simply being an immunosuppressive population unique to some cancers. Rather, MDSC expansion is a common response to all inflammatory processes, and the functions of MDSCs are highly dependent on the circumstances in which their expansion occurs. Like much of the host response to inflammation, the expansion of the MDSC population poses both beneficial opportunities as well as potential damaging costs to the host. MDSCs have potent innate immune effector cell function, and during periods of systemic insult (that is, cancer growth, sepsis) may actually serve to protect the host from opportunistic infectious insults. Manipulation of MDSC expansion and function offers unique opportunities, but also poses risks and uncertainties.
All supplementary materials are available online at https://doi.org/www.molmed.org .
MDSCs have been known for several decades under a number of different monikers, ranging from “natural suppressor cells” to “immature myeloid cells” to “suppressor macrophages” (4,5). These cells have been defined predominantly by their functional properties, and little is known about the specific identity of these cell populations. In mice, MDSCs have been characterized as an inducible cell population that expresses cell-surface CD11b and GR-1 antigens, does not or only weakly expresses other markers of mature myeloid cells (such as CD14 and MHC class II antigens), has increased expression of arginase (ARG) and inducible nitric oxide synthetase (iNOS), and produces large quantities of reactive oxygen species (ROS) and reactive nitrogen species (RNS) (6). These cells have the capacity to suppress predominantly antigen-specific CD8+ and CD4+ T-cell responses. Although these criteria are well accepted in the cancer literature, they are by no means highly specific or inclusive, and this ambiguity has often led to conflicting descriptions of their population and the argument that MDSCs originating in cancer may be different from those expanding during other acute and chronic inflammatory diseases, such as in trauma, burns, sepsis and autoimmune diseases (7).
Cell surface phenotyping of murine MDSC populations.a
Additional markers used
Gabrilovich et al., J. Immunol. 2001 (57)
Sinha et al., J. Immunol. 2005 (58)
MHC II, CD80/86, F4/80, CD11c,
Makarenkova et al., J. Immunol. 2006 (48)
MHC II, CD80/86, F4/80, CD11c, CD31
Delano et al., J. Exp. Med. 2007 (12)
Zhu et al., J. Immunol. 2007 (56)
Experimental autoimmune encephalomyelitis
Ly6C+, Ly6G+, Gr-1+, CD11b+
MHCII, CD80/86, F4/80, CD11c, CD31
Noel et al., Shock 2005 (31)
F4/80, CD115, CD117
Youn et al., J. Immunol. 2008 (14)
Ly6C+, Ly6G+, Gr-1+, CD11b+
CD80, CD115, CD124, PD-L1
Dolcetti et al., Eur. J. Immunol. 2010 (59)
Ly6C+, Ly6G+, Gr-1+, CD11b+
F4/80, CD11c, CD31, CD124
Within the CD11b+GR-1+ MDSC population, there have been several efforts by investigators to identify more highly enriched MDSC subpopulations that possess the immunosuppressive phenotype. Although the results have often been conflicting and remain controversial, several investigators have subdivided murine MDSCs into two subpopulations, termed polymorphonuclear (PMN)-MDSCs and mononuclear (MO)-MDSCs, on the basis of their relative expression of CD11b, Ly6G and Ly6C (13). MO-MDSCs are generally classified as CD11b+Gr-1intLy6G−Ly6Chigh cells, and they frequently express higher levels of F4/80, CD115 and CCR2 compared with PMN-MDSCs (13,14). These MDSCs are potently immunosuppressive, blocking antigen-specific CD8+ T-lymphocyte proliferation through an iNOS-mediated mechanism. In contrast, the PMN-MDSCs, classified as being CD11b+GR-1highLy6ClowLy6G+, are also immunosuppressive, but their mechanism(s) of action are thought to be more dependent on arginase and interferon-γ (6). Along the same lines, other investigators have subdivided MDSCs predominantly on the basis of the intensity of their GR-1 staining. For example, CD11b+GR-1high/bright subpopulations of MDSCs are primarily composed of Ly6G+Ly6C− populations and are the most mildly immunosuppressive, producing low levels of both iNOS and arginase (13,14). Conversely, the CD11b+GR-1intermed/dim population is comprised of mostly the MO-MDSCs with Ly6CbrightLy6G− expression and potent immunosuppressive phenotypes.
In humans, the problem of identifying MDSCs is exponentially greater. The absence of GR-1 in humans has made the identification of human MDSCs much more challenging. In addition, reduced access to secondary lymphoid organs and reticuloendothelial tissues has forced greater reliance on identifying these homologous populations in human blood, not the ideal location. Investigators have tried to recapitulate the PMN-MDSC and MO-MDSC phenotypes in humans by identifying CD11b+CD14−CD15+ cells with a PMN granulocyte morphology as the former (15). MO-MDSCs have been identified from a peripheral blood mononuclear cell fraction as being CD14+CD11b+HLA-DRlow/neg and secreting transforming growth factor-β (16). Other investigators have identified human MDSCs as CD11b+CD14−CD15+CD33+ or as Lineagel°w/−HLA-DR−CD33+CD11b+with suppressor phenotypes (2,17,18). Yet, as is obvious, these human criteria are even less specific than those used in mice, and the search for the elusive human MDSC continues.
MDSCs are More Than Adaptive Immune Suppressor Cells
Functional properties of MDSCs.a
Upregulated MDSC function
l-arginine depletion and NO scavenging
Inducible nitric oxide synthetase
l-arginine depletion and bactericidal
ROS/RNS production, nitrosylation of TCR, and bactericidal
M-CSF R (CD115)
Associated with suppressive activity
Th2 skewing and associated with suppressive activity
T-helper cell 2 skewing/antiinflammatory cytokines
Antiinflammatory; inhibits T-cell responses; causes TRC expansion
Direct antigen-specific CD8+ T-cell anergy
MHC restricted dissociation of CD3ζ/TCR signaling
Indirect antigen-specific CD8+ T-cell anergy
ARG, ROS, iNOS
Indirect antigen-specific CD4+ T-cell anergy
Suppression of graft-versus-host disease
IL-10 and TCR activation
Protection against infection
Protection against primary infection
Regulation of innate inflammation
Protection against secondary infection
Increases PMNs and inflammatory monocytes
Although the expansion of MDSCs in tumor-bearing hosts ultimately leads to T-cell inhibition, MDSCs possess machinery that would enhance their innate immune effector function. Corzo et al. have demonstrated that MDSCs from tumorbearing mice have upreg ulated p47phox and p91phox compared with their tumorfree counterparts, thereby increasing their ROS production versus non-tumor-bearing or naïve animals (20). In addition, there is evidence that increasing the inflammatory milieu in tumor-bearing mice further augments ROS production from MDSCs (26). Pande and colleagues have also shown that CD11b+GR-1+ cells isolated from tumor-bearing hosts produce increased myeloperoxidase and eosinophil peroxidase (27). These observations, coupled with the fact that both iNOS and ROS are vital components of innate immune effector-cell function and the massive expansion of these cells during tumor growth, sepsis and burns (12,28–32), indicate that MDSCs are poised to be excellent sentinels against infection in the face of systemic stress.
MDSCs obtained from tumor-bearing animals and patients produce increased amounts of the antiinflammatory and immunosuppressive cytokine IL-10 (33,34). This finding has led to the speculation that MDSCs may potentiate IL-10-dependent immune suppression and polarization of the T-helper 2 (Th2) adaptive immune response, as well as stimulate the development of regulatory T cells. However, we noted that MDSCs obtained from septic mice not only produced increased amounts of IL-10, but also produced increased amounts of the proinflammatory cytokine tumor necrosis factor α (TNFα), as well as the chemokines RANTES (regulated on activation normal T cell expressed and secreted) and MIP1α (macrophage inflammatory protein 1α) (12). Noel and Ogle also demonstrated that MDSCs isolated from the spleens of burned mice exhibited elevated production of TNFα, monocyte chemotactic protein-1 and stromal cell-derived factor 1 (SDF-1) (32). Thus, these MDSCs are eminently capable of producing a wide variety of inflammatory mediators, as well as the antiinflammatory IL-10.
These observations highlight several properties of MDSCs that have not received as much attention as their immunosuppressive properties on CD8+ and CD4+ T cells, which are of primary interest in the cancer literature. The biological role of MDSCs has only recently been explicitly associated with pathogen-surveillance or septic shock, although this tumor-induced myelopoietic expansion is in part regulated by inflammation and by the release of proinflammatory proteins such as S100A8/9 proteins and IL-1β (26,35). This hematopoietic link (described below) is critical to the host stress response because inflammation serves as a beacon for the primary innate immune response. Therefore, in settings of an uncontrolled systemic insult, such as metastatic tumor growth and sepsis, MDSCs and their unique properties may ultimately serve a role in protecting the host from infection through the production of increased antimicrobial products and by reducing the magnitude of the septic response (28).
Origins of MDSCs are in “Emergency Myelopoiesis”
MDSCs, like all other leukocytes, originate from self-renewing, long-term hematopoietic stem cells (HSCs). We previously found that polymicrobial sepsis causes myeloid cell expansion in the bone marrow, spleen, and lymph nodes (39). Because HSCs are the precursors for MDSCs, it was not surprising that we observed a tripling in the percentage and a doubling in the absolute number of the total HSC population within 36 hours of sepsis, and both the percentage and absolute number of HSCs remained elevated for at least 7 days. We also observed an increase in both the long-term and short-term HSC subpopulations by 36 hours post sepsis.
This expansion of HSCs in sepsis did not appear to be driven by traditional innate immune-signaling pathways. Mice deficient in toll-like receptor 4 (TLR4), type I interferon signaling, MyD88 and TRIF (TIR-domain-containing adaptor protein producing IFN [interferon] type I) signaling all had a perfectly normal expansion of their HSC populations in response to sepsis (39). Rather, the signals for HSC expansion appeared to originate at least partly in the bone marrow itself. Associated with the creation of niche space, there was a marked increased expression of c-kit, and passive immunization of mice with a blocking antibody to the c-kit receptor, prevented this expansion of HSCs and ultimately, MDSCs (manuscript in review, Scumpia and Kelly-Scumpia).
By asymmetrical division, long-term HSC give rise to short-term HSC that possess a limited capacity for self-renewal and finally develop into multipotent progenitors and then further into common myeloid progenitors that differentiate into megakaryocyte/erythroid progenitors or granulocyte/macrophage progenitors. We have also shown that during sepsis, there is a marked expansion (4- to 10-fold) in the numbers of these multipotent progenitor populations (manuscript in review).
Ostrand-Rosenberg and colleagues have recently argued that the inflammatory mediators IL-1, IL-6, prostaglandins and proinflammatory S100 proteins all drive this accumulation of MDSCs (3). Sander and Trautwein have demonstrated that MDSC expansion was dependent on IL-1R, IL-6 and gp130 (IL-6 superfamily signaling unit) signaling in sepsis (28). We also showed dependence on nuclear kB (factor NF-kB) signaling for a complete MDSC expansion (12). Such complexity and redundancy are not surprising given that the increased expression of these pathways is common to most if not all inflammatory processes.
Thus, it is not surprising that these MDSCs, which arise from intermediates between myeloid progenitors and mature myeloid cell populations, would increase in chronic inflammatory conditions. It is an oversimplification to suggest, however, that MDSCs are simply immature myeloid cells whose numbers expand during increased myelopoiesis. The dramatic increases in MDSC numbers cannot be simply explained by increased emergency myelopoiesis. Furthermore, it is not clear whether MDSCs in the spleen, liver and peripheral lymph nodes originate strictly from the bone marrow, but may also expand directly in organs owing to extramedullary hematopoiesis. Extramedullary hematopoiesis is frequently seen in both chronic inflammatory diseases and in cancer, and has also been reported in experimental sepsis (12). Thus, the origins of these MDSCs may not necessarily be bone marrow per se, and this has significant importance when it comes to therapeutic approaches intended to block the expansion of these populations in tumors or secondary lymphoid organs.
The other unresolved question is not what drives the myelopoiesis that provides the MDSC precursors during sepsis, cancer and chronic inflammatory events, but rather, what prevents the further differentiation and terminal disposition of these immature myeloid populations, and their resulting dramatic accumulation. Why are MDSCs accumulating in the spleen while the numbers of terminally differentiated macrophages, and dendritic cells either constant or declining? Furthermore, these cells possess an immunosuppressive phenotype not seen by similar GR-1+CD11b+ cells obtained from healthy animals (12,28). We have shown that if GR-1+ cells are removed from the spleens of septic mice and cultured in vitro with growth factors present in sepsis, they will readily differentiate into dendritic cells and macrophages (12). More importantly, Kusmartsev et al. harvested GR-1+ MDSCs from tumor-bearing animals and injected them into healthy hosts and observed that the injected cells rapidly lost their MDSC phenotype and could not be distinguished from endogenous, terminally differentiated macrophages and dendritic cells (40). Such data suggest that MDSCs retain the potential to further differentiate and mature, but in the host during chronic inflammation, associated with either an actively growing tumor or sepsis, the environmental milieu has ‘trapped’ these cells in an MDSC phenotype. Such cells are remarkably resistant to maturation signals. Although Gabrilovich and Kusmartsev et al. have shown that they can drive maturation of MDSCs from tumor bearing mice with all trans-retinoic acid (40,41), we were unable to do so in the presence of sepsis (unpublished observations). There have been a number of proposed mechanisms that can explain the failure of these cell populations to further mature and terminally differentiate. Lutz and colleagues have argued that the same factors involved in promoting the increased production of MDSC precursors are also responsible for their inability to differentiate into dendritic cells (42). One suggestion has been that elevated levels of vascular endothelial growth factor (VEGF) can prevent MDSCs from differentiating further into dendritic cells (43). It has been shown that administration of recombinant VEGF to healthy animals resulted in suppressed dendritic cell development associated with accumulation of GR-1+ immature MDSCs (44). Along the same lines, treatment of tumor-bearing animals and cancer patients with sunitinib, a tyrosine kinase inhibitor that targets the VEGF receptor among others, significantly reduces the numbers of MDSCs, although it does not appear to affect their maturation in vitro (45,46). Interestingly, sunitinib treatment also appears to reduce the immunosuppressive phenotype of MDSCs, by reducing the expression of the negative costimulatory molecule PDL-1 on MDSC (46). Whether this phenotypic change is associated with merely a greater differentiation of the cell population or a specific target of the tyrosine kinase inhibitor is still unknown.
Another circulating mediator, heat shock protein (HSP) 27, is associated with tumor progression and increased post-injury infection. Laudanski et al. have reported that elevated levels of HSP27 blocked the differentiation of myeloid precursors to dendritic cells and macrophages through a p38 MAP kinase-dependent pathway (47). These findings suggest that there are a number of inflammatory mediators that regulate the maturation of MDSCs, suggesting that therapeutic interventions may be possible but challenging.
MDSCs in Trauma and SEPSIS: Pathophysiologic or Beneficial?
Not surprisingly, MDSCs have been reported in the trauma and sepsis literature for several years. In 2004, Sherwood and colleagues reported on the presence of a “suppressor macrophage” population in the spleens of mice after burn injury (4). But the real breakthrough in linking MDSCs to trauma and sepsis came from the laboratory of Juan Ochoa and his colleagues at the University of Pittsburgh and Louisiana State University (48). These investigators observed a marked increase in a CD11b+GR-1+ population in the spleens of mice 24 hours after a traumatic injury. The investigators classified these cells as being MDSCs on the basis of their ability to suppress CD4+ T-cell proliferation, TCRζ chain and IL-2 expression, as well as their ability to produce large quantities of arginase. However, there were a number of physical characteristics of these cells that suggested that they differed at least qualitatively from MDSCs found in cancer and sepsis. These MDSCs had markedly higher MHC class II expression and lower class I expression, and very few cells expressed the immaturity marker, CD31. As shown in Figure 1, cytospins of this population revealed a predominantly “ringed-cell” phenotype consistent with a more mature PMN-MDSC phenotype.
We stumbled onto MDSCs in murine sepsis models fortuitously. Most sepsis models based on the cecal ligation and puncture method are designed to produce early, high mortality, and to use pharmacologic attempts to mitigate outcomes (49,50). We were interested not so much in the initial host response to sepsis, but in whether the septic animal had altered innate and adaptive immune processes that could explain their increased susceptibility to secondary infectious challenges: the theoretical basis behind the “second-hit phenomenon.” Investigation of this required that we develop a sepsis model that more accurately recapitulated outcomes to human sepsis that are on the order of 20–30% mortality and develop over several days. Developing a less lethal cecal ligation and puncture model, we observed, in animals surviving more than 3 days, a massive expansion of the CD11b+GR-1+ population not only in the spleen, but also in the peripheral lymph nodes and in the bone marrow (12). By 7 to 10 days after sepsis, almost 40% of the spleen was CD11b+GR-1+; in the bone marrow, the percentages increased to close to 90%, and in peripheral lymph nodes, the percentage increased to 3–5%. More dramatically, as the sepsis continued, splenomegaly developed, and the total numbers of these cells in the spleen increased more than 50-fold from healthy control animals.
Clearly, these cells were heterogenous (Figure 1), and included both immature and mature myeloid populations, as well as the putative MO-MDSC and PMN-MDSC subpopulations. The cells were clearly immunosuppressive and could both block a CD8+ T-cell proliferation as well as promote a Th1/Th2 shift in CD4+ T-cell cytokine production in vivo (12). Although less than 3% of the cells expressed MHC class II, almost 40% expressed CD31. More importantly, when GR-1+ splenocytes were harvested from septic mice and cultured ex vivo with growth factors (granulocyte-macrophage-colony stimulating factor and IL-4), they rapidly expanded into CD11c+ (dendritic) and F4/80+ (macrophage) populations. Surprisingly, when similar GR-1+ splenocytes were harvested from healthy control mice, these populations could not be encouraged to proliferate or differentiate into terminal cell populations.
Sander and Trautwein have convincingly argued that in septic conditions in which an exaggerated inflammatory response is lethal, blocking the MDSC expansion may also worsen outcome by promoting the inflammatory component. They showed that mice lacking gp130 and unable to signal through IL-6 failed to expand their MDSC population and had markedly higher mortalities to sepsis associated with increased inflammatory cytokine production (28). Furthermore, they showed that they could improve survival to sepsis when they reconstituted mice with CD11b+GR-1+ cells in their deficient animals. Thus, it is by no means clear whether the expansion in MDSCs contributes to sepsis immune suppression or prevents it. The answer is probably both, depending on the conditions.
The subsequent question is whether human trauma, burns and sepsis are also associated with expansion of homologous human MDSC populations. This is not known, for several reasons. First, there is little agreement about what constitutes an MDSC population in humans, in which the primary criterion of MDSC is a myeloid cell with T-cell suppressor function. Humans do not express the GR-1 antigen, and ring-shaped cells are generally not observed outside of leukemic conditions. Second, the blood compartment is not the most sensitive compartment to assess MDSC expansion, because blood appears to be a transient intermediate from either bone marrow expansion to secondary lymphoid and reticuloendothelial organs where they accumulate, or to where they are generated locally from extramedullary hematopoiesis. The processes of MDSC populations in organs and tissues of trauma and septic patients are technically challenging.
Can MDSC Expansion and Function Be Manipulated, and Should It Be?
The mechanisms that control the expansion and activity of MDSCs are influenced by multiple factors including cytokine/chemokine production from tumor, tumor stroma, and infiltrating T cells. NF-κB and JAK/STAT activation, in particular STAT3, are associated with both proliferation and survival of MDSCs, as well as the production of the S100 calcium-binding proteins, S100A8/9. These proteins subsequently bind and potentiate the NADPH complex and have also been shown to bind RAGE receptors (receptor for advanced glycosylation end-production) and TLR4. The net effect of this signaling cascade leads to the increased production of ROS and proinflammatory cytokines.
Because of the negative impact these increases in proinflammatory and innate immune responses have on T-cell immunity and tumor immunotherapy, strategies to modulate or inhibit the expansion of these cells have been actively pursued (2). One strategy that has been tested in the clinical setting is approached through maturation of MDSCs using the vitamin A metabolite, all-trans retinoic acid (41). Other potential strategies involve inhibiting the expansion of these cells through targeting of the vascular tumor stroma (anti-VEGF or sunitinib) (43) or hematopoiesis through targeting stem cell factor (55). However, the question remains: Is this expansion of MDSCs deleterious?
Certainly, in our hands and in the hands of others, these cells obtained from septic hosts have immunosuppressive activities on adaptive immunity, but if the expansion of MDSCs are the hosf’s attempt to correct and control the systemic insult, will we sacrifice enhanced innate immune responses at the expense of improved tumor immunity? Perhaps. In the setting of tumor growth, the net benefit of controlling the expansion of these cells will probably improve some aspects of clinical outcome, as dysregulated activity and expansion of these cells contribute to negative effects on the host. However, such actions are not without some theoretical risk of reducing immune surveillance. It is important to fully understand their role in host immunity, because attempts to control and prevent MDSC expansion in burn and sepsis preclinical models may actually increase susceptibility to both primary and secondary infection (Figure 4). As described above, Ogle’s group has demonstrated that after burn injury, mice are protected against secondary Pseudomonas aeruginosa infection, and depletion of MDSCs with gemcitabine blocks this effect (30). In addition, immunoneutralization of GR-1+ cells worsens survival to experimental sepsis (Figure 4) (28). Regardless, the goal of these therapies should be to strike a balance between improving adaptive immune responses and preserving innate immune function.
Future Direction and Goals
Though it is well accepted that a myelopoietic response to inflammation, infection and sepsis occurs, this response may be misunderstood. As described above, evidence from our laboratory and others suggest that this expansion of MDSCs may actually serve to protect the host through increased innate immunity and secondarily through suppression of cytokine/inflammatory responses (28,30). However, despite the demonstration of adaptive immune suppression in some of these studies, there is still significant controversy as to whether or not the MDSCs that arise in sepsis are truly MDSCs or a myelopoietic variant with similar characteristics (12). The greatest barrier to fully describing these cells despite differences between disease models and further, between species, lies in the lack of appropriate mechanistic studies, phenotypic markers and/or genomic signatures that can sufficiently unify scientific consensus. How similar are the MDSCs described in cancer to the MDSCs found to expand in autoimmunity or infection? Do the neutrophils described in clinical studies as CD11b+CD15+CD33+ have similar genomic/proteomic signatures as murine MDSCs? Or more importantly, does the expansion of MDSCs represent a conserved hematopoietic/myelopoietic response to systemic stress that is shaped by the disease process, but is driven to create a similar, albeit heterogenous, cell population? Mechanistic studies designed to address these concerns are critically important to our understanding not only of the biology of these cells but also the myelopoietic response to systemic insult.
Though largely dismissed before this decade, the MDSC has garnished tremendous scrutiny, despite the inability of investigators to identify a specific cell population. This examination has forced a reevaluation of the role that MDSCs play in the primary immune response and how they shape adaptive immunity. If the expansion of MDSCs were observed only as a solitary phenomenon in tumor studies, it would be clear how the interplay of the tumor and the normal inflammatory response would support the dramatic observations that have been described over the last decade. However, given the increasing knowledge regarding the myelopoioetic response to inflammation and the numerous pathological conditions in which very similar populations are expanding, the purpose of these cells cannot be defined so narrowly. Although T cells play undeniable roles in tumor and pathogen immuno-surveillance, we cannot discount the importance of the innate immune response and the possible role that T cells play in this process. Indeed, we and others have shown that as the host is compromised owing to some systemic pathologic insult, be it tumor growth, lupus or sepsis—the emergency hematopoietic response shifts toward myeloid lineages and expansion of myeloid cell precursors. Moreover, there are likely important differences in the immunosuppressive, proinflammatory mediators expressed and stored within various MDSCs, depending on the nature of the chronic inflammation. Some of these mediators may even have the potential to induce acute changes in hemodynamic responses through modulation of endothelial cells as shown by Pande et al. (27). The expansion of MDSCs is a critical component of this response that can have obvious harmful effects. Therefore, there remains a compelling need to further understand the role MDSCs play before we consider manipulating them in the diverse clinical settings in which they arise.
The authors declare that they have no competing interests as defined by Molecular Medicine, or other interests that might be perceived to influence the results and discussion reported in this paper.
Supported in part by grants R01 GM-40586-22 and R01 GM-81923-03 from the National Institute of General Medical Sciences. AG Cuenca, MJ Delano, C Moreno and KM Kelly-Scumpia were supported by a T32 training grant in burns and trauma (T32 GM-08721-11). AG Cuenca was also supported by an individual National Research Service Award (F32 GM-093665-01) from the National Institute of General Medical Sciences.
The authors acknowledge the contributions of R Hotchkiss, Washington University in St. Louis, for providing the deidentified and anonymous tissue blocks. In addition, we thank J Phillips, P Heyworth and D LaFace from DNAX/Merck Biopharma for the MDL-1 staining, as well as the fruitful discussions.
The authors have no financial conflicts with the submission.
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