MDSC suppress T cell activation by multiple mechanisms. They suppress CD4+
T cells by their uptake of arginine and high intracellular level of arginase that depletes their surroundings of arginine, an essential amino acid for T cell activation (42
). MDSC-produced ROS and peroxynitrite inhibit CD8+
T cells by catalyzing the nitration of the TCR and thereby preventing T cell-peptide-MHC interactions (57
The development and function of most MDSC require IFN-γ
. Both monocytic MDSC (CD11b+
) and granulocytic MDSC were reported to be IFN-γ
dependent; however, monocytic MDSC suppress via NO (ROS undetectable), whereas granulocytic MDSC suppress via ROS (NO undetectable) (39
). Earlier studies also demonstrated that NO (56
) and ROS production are IFN-γ
). However, IFN-γ
may not be essential for all MDSC, because MDSC from IFN-γ
receptor- deficient and -sufficient mice are equally suppressive for T cell activation (51
), (P. Sinha and S. Ostrand-Rosenberg, unpublished observations).
The immunosuppressive molecule TGF-β
has also been implicated in MDSC function. MDSC with the phenotype CD11b+
(where “int” is “intermediate”) and induced by a mouse fibrosarcoma or colon carcinoma when stimulated with IL-13 through the IL-13Rα
are activated to produce TGF-β
). In the same report, CD11b+
MDSC did not produce suppressive TGF-β
. Experiments with a transplanted and spontaneous mammary carcinoma demonstrated increased levels of TGF-β
in the tumor microenvironment if the tumor cells were deficient for the type II TGF-β
receptor. These authors demonstrated that a deficiency in the receptor resulted in an increase in CXCL5 in the tumor microenvironment. CXCL5, in turn, chemoattracted CXCR2-expressing Gr1+
MDSC. Because Gr1+
cells from tumor-bearing but not tumor-free mice produced high levels of TGF-β
, tumor-infiltrating MDSC were the likely source of the heightened TGF-β
in the tumor microenvironment. In addition to demonstrating that some MDSC use TGF-β
to suppress, these reports indicate that at least some tumor-driven Gr1+
cells are distinct from normally differentiating myeloid cells (8
MDSC also suppress by down-regulating the TCR-associated ζ
), a phenomenon that occurs in most cancer patients (77
) and is caused by inflammation (78
). In the absence of the ζ
T cells are unable to transmit the required signals for activation.
Two additional suppressive mechanisms have been recently identified. MDSC down-regulate L-selectin (CD62L), a plasma membrane molecule necessary for the homing of naive T cells to lymph nodes. As a result, activation of CD4+ and CD8+ T cells is reduced because they are unable to migrate to lymph nodes where they would normally be activated by tumor Ags (E. M. Hanson, V. K. Clements, P. Sinha, D. Ilkovitch, and S. Ostrand-Rosenberg. Myeloid-derived suppressor cells down-regulate L-selectin expression on CD4+ and CD8+ T cells. Submitted for publication).
Recent work demonstrates that MDSC also block T cell activation by depriving the environment of cysteine, an amino acid that is essential for T cell activation. T cells lack the enzyme to convert methionine to cysteine and the membrane transporter to import cystine, which could be reduced intracellularly to cysteine, and therefore must obtain their cysteine from extracellular sources. Under healthy conditions, APCs (i.e., DC and macrophages) synthesize cysteine from methionine and import extracellular cystine and convert it to cysteine. Surplus cysteine is then exported during Ag presentation and imported by T cells. MDSC are also unable to convert methionine to cysteine, so they are fully dependent on importing cystine for conversion to cysteine. When MDSC are present in high concentrations they import most of the available cystine, depriving DC and macrophages of cystine. Because MDSC do not export cysteine, their immediate environment is cysteine deficient and T cells are unable to synthesize the necessary proteins for activation (M. Srivastava, P. Sinha, and S. Ostrand-Rosenberg. Myeloid-derived suppressor cells inhibit T cell activation by sequestering cystine and cysteine. Submitted for publication).
diagrams the target cells impacted by MDSC and the suppressive mechanisms used by MDSC and illustrates the wide-ranging impact that these cells have on the immune system.
FIGURE 2 MDSC suppress antitumor immunity through a variety of diverse mechanisms. T cell activation is suppressed by the production of arginase and ROS, the nitration of the TCR, cysteine deprivation, and the induction of Tregs. Innate immunity is impaired by (more ...)