Role of l‐arginine and CD11b+Gr‐1+ cells in immunosuppression induced by Heligmosomoides polygyrus bakeri

Abstract

Myeloid‐derived suppressor cells (MDSCs) are heterogeneous population of monocyte and granulocyte progenitors that are highly suppressive against T cells. In BALB/c mice infected with a nematode Heligmosomoides polygyrus bakeri, we studied the dynamics of MDSCs, identified as CD11b+Gr‐1+, induction in different tissues along with the development of parasite infection. We observed that MDSC‐like cells are induced both by larvae and adult stages of H polygyrus bakeri. Gr‐1+ cells of suppressive phenotype are recruited in the bone marrow, peripheral blood and peritoneal cavity during histotropic phase of infection and are present at that time in the intestine wall, where worms reside. Later, during intestinal phase, suppressive Gr‐1+ cells increased in mesenteric lymph nodes and the spleen. l‐arginine metabolism was important for the protective immunity, and parasite‐induced Gr‐1+ cells showed elevated arginase‐1 and iNOS expression. Inhibition of arginase‐1 and l‐arginine administration caused reduced level of infection that coincided with weaker suppressive phenotype of Gr‐1+ cells. We identified that l‐arginine pathway activation and induction of MDSC‐like cells characterize immunosuppressive state during H polygyrus bakeri infection in mice. Our findings confirm the role of MDSCs in parasitic infections and point l‐arginine pathway as a potential target for immunomodulation during nematode infections.

Myeloid-Derived Suppressor Cells: The Expanding World of Helminth Modulation of the Immune System

“…A study performed in BALB/c mice confirmed that MDSC expand during primary H. polygyrus bakeri infection (65). This paper demonstrated that CD11b + Gr1 + cells increase in the bone marrow, blood, and peritoneal cavity early after infection.…”

“…We observed that CD4 + GATA3 + T cells increased significantly in the MLN after both primary and challenge infections compared to uninfected mice, but their numbers were significantly lower after primary infection compared to challenge infection. Notably, we observed dramatic increases in CD11b hi Gr1 hi F4/ 80cells in the MLN and spleen after primary H. polygyrus bakeri infection while there were no significant increases in this cell population after challenge infection (51,65). This indicates that MDSC expand at the site of infection as well as systemically after primary infection but not after challenge infection.…”

Infection-Derived Monocytic MDSCs Require TGF-β to Suppress Filarial-Specific IFN-γ But Not IL-13 Release by Filarial-Specific CD4+ T Cells In Vitro

“…Two subsets of MDSCs, the monocytic MDSCs (Mo-MDSCs, CD11b + Ly6C + Ly6G -) and the polymorphonuclear MDSCs (PMN-MDSCs, CD11b + Ly6C int/lo Ly6G + ) have been identified in patients and murine models of disease. These include cancer, systemic inflammation and sepsis, autoimmune diseases as well as bacterial, viral and parasitic infections (18)(19)(20)(21)(22)(23)(24)(25)(26). Mo-MDSCs and PMN-MDSCs are reported to suppress T and B cell responses through receptors, cytokines, or soluble factors as reviewed (20,27).…”

Amino acid metabolism in immune cells: essential regulators of the effector functions, and promising opportunities to enhance cancer immunotherapy

“…In sepsis, MDSCs attenuate T cell function by metabolizing arginine to toxic molecules that impair T cell ζ chain expression [ 282 ]. In parasitic infection, MDSCs are induced by both larval and adult stages of Heligmosomoides polygyrus bakeri and increase their expression of arginase-1 and iNOS, which suggests that metabolism of arginine contribute to the maintenance of immunosuppressive function of MDSCs [ 283 ]. Another study observed that arginase-1 expressing MDSCs effectively inhibit the T cell response to alleviate tissue injury following hepatitis B viral infection [ 284 ].…”