MyD88-dependent expansion of an immature GR-1+CD11b+ population induces T cell suppression and Th2 polarization in sepsis

Abstract

Polymicrobial sepsis alters the adaptive immune response and induces T cell suppression and Th2 immune polarization. We identify a GR-1+CD11b+ population whose numbers dramatically increase and remain elevated in the spleen, lymph nodes, and bone marrow during polymicrobial sepsis. Phenotypically, these cells are heterogeneous, immature, predominantly myeloid progenitors that express interleukin 10 and several other cytokines and chemokines. Splenic GR-1+ cells effectively suppress antigen-specific CD8+ T cell interferon (IFN) γ production but only modestly suppress antigen-specific and nonspecific CD4+ T cell proliferation. GR-1+ cell depletion in vivo prevents both the sepsis-induced augmentation of Th2 cell–dependent and depression of Th1 cell–dependent antibody production. Signaling through MyD88, but not Toll-like receptor 4, TIR domain–containing adaptor-inducing IFN-β, or the IFN-α/β receptor, is required for complete GR-1+CD11b+ expansion. GR-1+CD11b+ cells contribute to sepsis-induced T cell suppression and preferential Th2 polarization.

Granulocytic Myeloid-Derived Suppressor Cells Accumulate in Human Placenta and Polarize toward a Th2 Phenotype

“…We found that plaGR-MDSCs led to a polarization of CD4 + T cells toward a Th2 phenotype. This is in line with studies in mice and humans showing an association between MDSC count and Th2 cytokine expression (15,(57)(58)(59). The present study, however, is to our knowledge the first to show a direct impact of MDSCs on T cell polarization in humans.…”

“…They are part of normal hematopoiesis but are dramatically expanded and activated in many types of cancer in humans and mice (11)(12)(13)(14) as well as under other pathological conditions such as infection (15,16), trauma (17), or transplant rejection (18,19). GR-MDSCs express the common myeloid marker CD33 and the granulocytic lineage markers CD66b or CD15 whereas they do not exhibit monocytic Ags such as CD14 and HLA-DR (10,20,21).…”

Expansion of Tfh‐like cells during chronic Salmonella exposure mediates the generation of autoimmune hypergammaglobulinemia in MyD88‐deficient mice

“…Similarly, MyD88 has been postulated to provide a negative signal for Th2-cell development via TLR signaling in dendritic cells [24,25]. However, in a model of polymicrobial sepsis, the MyD88-dependent accumulation of Gr-1 1 CD11b 1 cells in the spleen-mediated Th2-cell-dependent hyper-B-cell responses [26]. Thus, the role of MyD88-dependent innate signaling for the regulation of B-cell responses in the inflammatory condition remains controversial, especially the role of CD11b 1 Gr-1 1 myeloid cells.…”

Premetastatic milieu explained by TLR4 agonist-mediated homeostatic inflammation

“…In addition, they not only favor IL-10 production, but also suppress IL-12 secretion in macrophages, providing Th2-like responses. 20 Moreover, Gr-1 1 CD11b 1 myeloid cells directly suppress T-cell immunity by Nox-2-mediated generation of ROS. 21 Carcinoma-associated fibroblasts may also participate in cancer immunology.…”