Myeloid-Derived Suppressor Cells in Murine Retrovirus-Induced AIDS Inhibit T- and B-Cell Responses<i>In Vitro</i>That Are Used To Define the Immunodeficiency

Green, Kathy A.; Cook, William J.; Green, William R.

doi:10.1128/jvi.01547-12

Cited by 49 publications

(97 citation statements)

References 107 publications

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“…Comparison of cells from wild-type (WT), iNOS Ϫ/Ϫ , and VISTA Ϫ/Ϫ B6 mice (32) at 5 wpi confirmed VISTA and CD11b coexpression by the highly enriched monocytic Ly6C ϩ MDSC population we have previously described (10), as depicted in the representative experiment in Fig. 1 (consistent with the average MFI and percent positivity over three experiments [legend to Fig.…”

Section: Ly6csupporting

confidence: 55%

“…We recently defined these monocytic MDSCs as Gr-1 ϩ Ly6C ϩ/hi Ly6G ϩ/Ϫ/low CD11b ϩ with strong ex vivo inhibition of T-and B-cell responses used to measure LP-BM5-induced immunodeficiency (10). This robust direct MDSCinduced inhibition of B-cell responsiveness is novel for murine retrovirus-induced immunosuppression, if not generally.…”

Section: Ly6cmentioning

confidence: 99%

“…Limited reports indicate MDSC regulation of autoimmunity (3) and selected viral infections (4-7), including only recently, retroviral infections and murine and human AIDS (8)(9)(10)(11). Murine MDSCs are relatively immature and heterogeneous, but all express Gr-1 and CD11b.…”

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confidence: 99%

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Selective Involvement of the Checkpoint Regulator VISTA in Suppression of B-Cell, but Not T-Cell, Responsiveness by Monocytic Myeloid-Derived Suppressor Cells from Mice Infected with an Immunodeficiency-Causing Retrovirus

Green

Wang

Noelle

et al. 2015

J Virol

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Ly6Cϩ/hi and granulocytic/polymorphonuclear-leukocyte-like Ly6G ϩ/hi Ly6C ϩ/Ϫ/lo , use differential suppressive mechanisms to inhibit T cells (12,13). MDSC inhibition of B-cell responses is studied rarely, if at all.Retroviruses are adept at co-opting immunoregulatory mechanisms. Human immunodeficiency virus type 1/simian immunodeficiency virus induction of PD-1 downregulates T effector cells (14,15), and murine Friend retrovirus infection-induced PD-1 and Tim-3 affect pathogenesis and retroviral loads (16, 17), sometimes with "functionless" T cells occurring (14,15). Viral infections can also induce CD4 ϩ FoxP3 ϩ regulatory T (Treg) cells (18), including in LP-BM5 murine retroviral pathogenesis (19-21). By 5 weeks postinfection (wpi), LP-BM5 causes profound immunodeficiency, with increased susceptibility to "opportunistic" infections and B-cell lymphomas (22, 23). Immunodeficiency requires "pathogenic" CD4ϩ T-effector cell expression of CD154 and ligation of CD40 (22,24,25), and PD-1/PD-L1 and IL-10 downregulate effector T-cell activity (21,26).A CD11b ϩ FcR␥III/II ϩ myeloid cell subset expands during LP-BM5 pathogenesis (26, 27). We recently defined these monocytic MDSCs as Gr-1 ϩ Ly6C ϩ/hi Ly6G ϩ/Ϫ/low CD11b ϩ with strong ex vivo inhibition of T-and B-cell responses used to measure LP-BM5-induced immunodeficiency (10). This robust direct MDSCinduced inhibition of B-cell responsiveness is novel for murine retrovirus-induced immunosuppression, if not generally. Also, a new negative-checkpoint regulatory ligand, VISTA (V-domain Ig suppressor of T-cell activation) (28-30), also designated PD-1H (31), with homology to PD-L1 has been defined. VISTA can be highly upregulated on myeloid-derived cells and can inhibit T-cell responses in autoimmunity and antitumor immunity in a nonredundant manner with PD-L1 (28).At 5 wpi with LP-BM5, regarding cell surface VISTA expression, the percentage of VISTA ϩ spleen cells had not expanded but VISTA mean fluorescence intensity (MFI) increased and the shape of the positive peak changed, consistent with the dominance of CD4 T-cell-expressed VISTA in uninfected B6 mice (28) and with CD11b ϩ VISTA ϩ cell expansion. Comparison of cells from wild-type (WT), iNOS Ϫ/Ϫ , and VISTA Ϫ/Ϫ B6 mice (32) at 5 wpi confirmed VISTA and CD11b coexpression by the highly enriched monocytic Ly6C ϩ MDSC population we have previously described (10), as depicted in the representative experiment in Fig. 1 (consistent with the average MFI and percent positivity over three experiments [legend to Fig. 1]). Of note, there was minimal contamination with other cells, particularly CD4ϩ Treg cells (legend to Fig. 1). Interestingly, similar monocytic MDSCs could be isolated from the spleens of uninfected mice. These MDSCs expressed levels of VISTA approaching (and, over three repeat experiments, not significantly statistically significantly different from) that of their

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Section: Ly6csupporting

confidence: 55%

Section: Ly6cmentioning

confidence: 99%

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Selective Involvement of the Checkpoint Regulator VISTA in Suppression of B-Cell, but Not T-Cell, Responsiveness by Monocytic Myeloid-Derived Suppressor Cells from Mice Infected with an Immunodeficiency-Causing Retrovirus

Green

Wang

Noelle

et al. 2015

J Virol

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“…It would be interesting, given the results of the effect of I-152 treatment on peritoneal macrophages obtained here, to test the activity of the molecule against other cells of the myeloid lineage in the context of LP-BM5 retrovirus-induced disease. Specifically, recent reports have detailed augmented monocytic myeloid-derived suppressor cell (M-MDSC) production during LP-BM5-induced disease, including immunodeficiency (69)(70)(71)(72). Because the mechanism of inhibition of T-cell responses by these M-MDSCs for inhibition of T-cell responses was fully dependent on iNOS/NO, whereas iNOS/NO was responsible for about 50% of the inhibition of B-cell responses, it would be interesting to study I-152 treatment to determine whether M-MDSC numbers and suppressive activity can be increased or decreased in LP-BM5-infected mice.…”

Section: Discussionmentioning

confidence: 99%

Glutathione Depletion Is Linked with Th2 Polarization in Mice with a Retrovirus-Induced Immunodeficiency Syndrome, Murine AIDS: Role of Proglutathione Molecules as Immunotherapeutics

Brundu

Palma

Picceri

et al. 2016

J Virol

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Injection of the LP-BM5 murine leukemia virus into mice causes murine AIDS, a disease characterized by many dysfunctions of immunocompetent cells. To establish whether the disease is characterized by glutathione imbalance, reduced glutathione (GSH) and cysteine were quantified in different organs. A marked redox imbalance, consisting of GSH and/or cysteine depletion, was found in the lymphoid organs, such as the spleen and lymph nodes. Moreover, a significant decrease in cysteine and GSH levels in the pancreas and brain, respectively, was measured at 5 weeks postinfection. The Th2 immune response was predominant at all times investigated, as revealed by the expression of Th1/Th2 cytokines. Furthermore, investigation of the activation status of peritoneal macrophages showed that the expression of genetic markers of alternative activation, namely, Fizz1, Ym1, and Arginase1, was induced. Conversely, expression of inducible nitric oxide synthase, a marker of classical activation of macrophages, was detected only when Th1 cytokines were expressed at high levels. In vitro studies revealed that during the very early phases of infection, GSH depletion and the downregulation of interleukin-12 (IL-12) p40 mRNA were correlated with the dose of LP-BM5 used to infect the macrophages. Treatment of LP-BM5-infected mice with N-(N-acetyl-L-cysteinyl)-S-acetylcysteamine (I-152),an N-acetyl-cysteine supplier, restored GSH/cysteine levels in the organs, reduced the expression of alternatively activated macrophage markers, and increased the level of gamma interferon production, while it decreased the levels of Th2 cytokines, such as IL-4 and IL-5. Our findings thus establish a link between GSH deficiency and Th1/Th2 disequilibrium in LP-BM5 infection and indicate that I-152 can be used to restore the GSH level and a balanced Th1/Th2 response in infected mice. IMPORTANCEThe first report of an association between Th2 polarization and alteration of the redox state in LP-BM5 infection is presented. Moreover, it provides evidence that LP-BM5 infection causes a decrease in the thiol content of peritoneal macrophages, which can influence IL-12 production. The restoration of GSH levels by GSH-replenishing molecules can represent a new therapeutic avenue to fight this retroviral infection, as it reestablishes the Th1/Th2 balance. Immunotherapy based on the use of pro-GSH molecules would permit LP-BM5 infection and probably all those viral infections characterized by GSH deficiency and a Th1/ Th2 imbalance to be more effectively combated. Infection with the LP-BM5 murine leukemia virus causes a profound and broad immunodeficiency in susceptible mouse strains, such as C57BL/6 (B6) mice. This disease is known as murine AIDS (MAIDS) and is characterized by early polyclonal T-and B-cell activation, splenomegaly, lymphadenopathy, hypergammaglobulinemia, decreased T-and B-cell responses, increased susceptibility to opportunistic pathogens, and the development of terminal B-cell lymphomas and neurological dysfunctions (1-4). MAIDS is charact...

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“…In humans, MDSCs are HLA-DR Ϫ or HLA-DR low and CD11b ϩ , CD33 ϩ , or CD15 ϩ (19). MDSCs are immunosuppressive and have been shown to suppress the functions of NK cells, T cells, and B cells (20,21). The suppressive activity of MDSCs appears to be inversely related to the expression of the programmed death 1 protein (PD-1), as MDSCs from PD-1 Ϫ/Ϫ mice are more immunosuppressive than those from wild-type mice (20).…”

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Myeloid-Derived Suppressor Cells Impair Alveolar Macrophages through PD-1 Receptor Ligation during Pneumocystis Pneumonia

2015

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Myeloid-derived suppressor cells (MDSCs) were recently found to accumulate in the lungs during Pneumocystis pneumonia (PcP). Adoptive transfer of these cells caused lung damage in recipient mice, suggesting that MDSC accumulation is a mechanism of pathogenesis in PcP. In this study, the phagocytic activity of alveolar macrophages (AMs) was found to decrease by 40% when they were incubated with MDSCs from Pneumocystis-infected mice compared to those incubated with Gr-1 ؉ cells from the bone marrow of uninfected mice. The expression of the PU.1 gene in AMs incubated with MDSCs also was decreased. This PU.1 downregulation was due mainly to decreased histone 3 acetylation and increased DNA methylation caused by MDSCs. MDSCs were found to express high levels of PD-L1, and alveolar macrophages (AMs) were found to express high levels of PD-1 during PcP. Furthermore, PD-1 expression in AMs from uninfected mice was increased by 18-fold when they were incubated with MDSCs compared to those incubated with Gr-1 ؉ cells from the bone marrow of uninfected mice. The adverse effects of MDSCs on AMs were diminished when the MDSCs were pretreated with anti-PD-L1 antibody, suggesting that MDSCs disable AMs through PD-1/PD-L1 ligation during PcP.

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Myeloid-Derived Suppressor Cells in Murine Retrovirus-Induced AIDS Inhibit T- and B-Cell ResponsesIn VitroThat Are Used To Define the Immunodeficiency

Cited by 49 publications

References 107 publications

Selective Involvement of the Checkpoint Regulator VISTA in Suppression of B-Cell, but Not T-Cell, Responsiveness by Monocytic Myeloid-Derived Suppressor Cells from Mice Infected with an Immunodeficiency-Causing Retrovirus

Selective Involvement of the Checkpoint Regulator VISTA in Suppression of B-Cell, but Not T-Cell, Responsiveness by Monocytic Myeloid-Derived Suppressor Cells from Mice Infected with an Immunodeficiency-Causing Retrovirus

Glutathione Depletion Is Linked with Th2 Polarization in Mice with a Retrovirus-Induced Immunodeficiency Syndrome, Murine AIDS: Role of Proglutathione Molecules as Immunotherapeutics

Myeloid-Derived Suppressor Cells Impair Alveolar Macrophages through PD-1 Receptor Ligation during Pneumocystis Pneumonia

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