Functional proteomic analysis for regulatory T cell surveillance of the HIV-1-infected macrophage.
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.
Department of Pharmacology, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.
Xiuyan
X
Huang
David K
DK
Stone
Fang
F
Yu
Yaoying
Y
Zeng
Howard E
HE
Gendelman
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D057809:HEK293 Cells; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D018448:Models, Immunological; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010455:Peptides / Q000032:analysis / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D015398:Signal Transduction / Q000276:immunology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014452:Ubiquitins / Q000378:metabolism
D016207:Cytokines; C489550:G1p2 protein, mouse; D010455:Peptides; D014452:Ubiquitins; D000242:Cyclic AMP; D052247:Nitric Oxide Synthase Type II; D053148:Caspase 3