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Functional proteomic analysis for regulatory T cell surveillance of the HIV-1-infected macrophage.

Huang X, Stone DK, Yu F, Zeng Y, Gendelman HE - J. Proteome Res. (2010)

Bottom Line: Reduction in virus release paralleled the upregulation of interferon-stimulated gene 15, an ubiquitin-like protein involved in interferon-mediated antiviral immunity.Taken together, Treg affects a range of virus-infected MP functions.The observations made serve to challenge the dogma of solitary Treg immune suppressor functions and provides novel insights into how Treg affects adaptive immunosurveillance for control of end organ diseases, notably neurocognitive disorders associated with advanced viral infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.

ABSTRACT
Regulatory T cells (Treg) induce robust neuroprotection in murine models of neuroAIDS, in part, through eliciting anti-inflammatory responses for HIV-1-infected brain mononuclear phagocytes (MP; macrophage and microglia). Herein, using both murine and human primary cell cultures in proteomic and cell biologic tests, we report that Treg promotes such neuroprotection by an even broader range of mechanisms than previously seen including inhibition of virus release, killing infected MP, and inducing phenotypic cell switches. Changes in individual Treg-induced macrophage proteins were quantified by iTRAQ labeling followed by mass spectrometry identifications. Reduction in virus release paralleled the upregulation of interferon-stimulated gene 15, an ubiquitin-like protein involved in interferon-mediated antiviral immunity. Treg killed virus-infected macrophages through caspase-3 and granzyme and perforin pathways. Independently, Treg transformed virus-infected macrophages from an M1 to an M2 phenotype by down- and up- regulation of inducible nitric oxide synthase and arginase 1, respectively. Taken together, Treg affects a range of virus-infected MP functions. The observations made serve to challenge the dogma of solitary Treg immune suppressor functions and provides novel insights into how Treg affects adaptive immunosurveillance for control of end organ diseases, notably neurocognitive disorders associated with advanced viral infection.

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Treg-induced infected BMM elicits neuroprotection. Tubulin staining shows persevered neuronal dendrites in groups cultured with both CM1 (upper panel) and CM2 (bottom panel) from Treg treated HIV-1/VSV-infected BMM, which was not seen in Tcon derived CM. Moreover, CM2 from the Tcon treated group exhibits more toxicity than the infected group, which suggests that the proinflammatory cytokines are more destructive than viral proteins. White scale bar represents 50 μm.
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fig6: Treg-induced infected BMM elicits neuroprotection. Tubulin staining shows persevered neuronal dendrites in groups cultured with both CM1 (upper panel) and CM2 (bottom panel) from Treg treated HIV-1/VSV-infected BMM, which was not seen in Tcon derived CM. Moreover, CM2 from the Tcon treated group exhibits more toxicity than the infected group, which suggests that the proinflammatory cytokines are more destructive than viral proteins. White scale bar represents 50 μm.

Mentions: Given the multiple mechanisms of Treg presented herein used to modulate HIV-1/VSV infected macrophages (Supplemental Figure 7, Supporting Information), we expected that Treg must have neuroprotective roles due to their abilities to inhibit viremia and resolve inflammation. Indeed, our lab recently showed the neuroprotective properties of Treg in an HIVE model.(9) To confirm this anticipation, we used conditioned medium to treat primary neurons in vitro. Neuroprotection is readily observed in Treg-treated BMM groups (Figure 6). Comparisons between neurons treated with conditioned media from HIV-1/VSV infected BMM in the absence or presence of Treg and Tcon are shown (Figure 6 and Supplemental Table 1, Supporting Information). Furthermore, addition of media from uninfected macrophages was not observed to result in any neurotoxicity (Figure 6 and data not shown).


Functional proteomic analysis for regulatory T cell surveillance of the HIV-1-infected macrophage.

Huang X, Stone DK, Yu F, Zeng Y, Gendelman HE - J. Proteome Res. (2010)

Treg-induced infected BMM elicits neuroprotection. Tubulin staining shows persevered neuronal dendrites in groups cultured with both CM1 (upper panel) and CM2 (bottom panel) from Treg treated HIV-1/VSV-infected BMM, which was not seen in Tcon derived CM. Moreover, CM2 from the Tcon treated group exhibits more toxicity than the infected group, which suggests that the proinflammatory cytokines are more destructive than viral proteins. White scale bar represents 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108468&req=5

fig6: Treg-induced infected BMM elicits neuroprotection. Tubulin staining shows persevered neuronal dendrites in groups cultured with both CM1 (upper panel) and CM2 (bottom panel) from Treg treated HIV-1/VSV-infected BMM, which was not seen in Tcon derived CM. Moreover, CM2 from the Tcon treated group exhibits more toxicity than the infected group, which suggests that the proinflammatory cytokines are more destructive than viral proteins. White scale bar represents 50 μm.
Mentions: Given the multiple mechanisms of Treg presented herein used to modulate HIV-1/VSV infected macrophages (Supplemental Figure 7, Supporting Information), we expected that Treg must have neuroprotective roles due to their abilities to inhibit viremia and resolve inflammation. Indeed, our lab recently showed the neuroprotective properties of Treg in an HIVE model.(9) To confirm this anticipation, we used conditioned medium to treat primary neurons in vitro. Neuroprotection is readily observed in Treg-treated BMM groups (Figure 6). Comparisons between neurons treated with conditioned media from HIV-1/VSV infected BMM in the absence or presence of Treg and Tcon are shown (Figure 6 and Supplemental Table 1, Supporting Information). Furthermore, addition of media from uninfected macrophages was not observed to result in any neurotoxicity (Figure 6 and data not shown).

Bottom Line: Reduction in virus release paralleled the upregulation of interferon-stimulated gene 15, an ubiquitin-like protein involved in interferon-mediated antiviral immunity.Taken together, Treg affects a range of virus-infected MP functions.The observations made serve to challenge the dogma of solitary Treg immune suppressor functions and provides novel insights into how Treg affects adaptive immunosurveillance for control of end organ diseases, notably neurocognitive disorders associated with advanced viral infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.

ABSTRACT
Regulatory T cells (Treg) induce robust neuroprotection in murine models of neuroAIDS, in part, through eliciting anti-inflammatory responses for HIV-1-infected brain mononuclear phagocytes (MP; macrophage and microglia). Herein, using both murine and human primary cell cultures in proteomic and cell biologic tests, we report that Treg promotes such neuroprotection by an even broader range of mechanisms than previously seen including inhibition of virus release, killing infected MP, and inducing phenotypic cell switches. Changes in individual Treg-induced macrophage proteins were quantified by iTRAQ labeling followed by mass spectrometry identifications. Reduction in virus release paralleled the upregulation of interferon-stimulated gene 15, an ubiquitin-like protein involved in interferon-mediated antiviral immunity. Treg killed virus-infected macrophages through caspase-3 and granzyme and perforin pathways. Independently, Treg transformed virus-infected macrophages from an M1 to an M2 phenotype by down- and up- regulation of inducible nitric oxide synthase and arginase 1, respectively. Taken together, Treg affects a range of virus-infected MP functions. The observations made serve to challenge the dogma of solitary Treg immune suppressor functions and provides novel insights into how Treg affects adaptive immunosurveillance for control of end organ diseases, notably neurocognitive disorders associated with advanced viral infection.

Show MeSH
Related in: MedlinePlus