Soluble ligands for the NKG2D receptor are released during HIV-1 infection and impair NKG2D expression and cytotoxicity of NK cells

Giulia Matusali, Hyppolite Kuekou Tchidjou, Giuseppe Pontrelli, Stefania Bernardi, Gabriella D'Ettorre, Vincenzo Vullo, Anna Rita Buonomini, Massimo Andreoni, Angela Santoni, Cristina Cerboni, Margherita Doria

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

In humans, the interaction of the natural killer group 2 member D (NKG2D)-activating receptor on natural killer (NK) and CD8+ T cells with its major histocompatibility complex class I-related chain (MIC) and UL16 binding protein (ULBP) ligands (NKG2DLs) promotes recognition and elimination of stressed cells, such as tumor or infected cells. Here, we investigated the capacity of HIV-1 to modulate NKG2DL expression and escape NGK2D-mediated immunosurveillance. In CD4+ T lymphocytes, both cell surface expression and release of MICA, MICB, and ULBP2 were up-regulated >2-fold by HIV-1 infection. In HIV-infected CD4+ T lymphocytes or Jurkat T-cell lines, increased shedding of soluble NKG2DLs (sNKG2DLs) was impaired by a matrix metalloproteinase inhibitor (MMPI). Moreover, naive HIV+ patients displayed increased plasma sMICA and sULBP2 levels and reduced NKG2D expression on NK and CD8+ T cells compared to patients receiving highly active antiretroviral therapy (HAART) or healthy donors. In individual patients, HAART uptake resulted in the drop of sNKG2DL and recovery of NKG2D expression. Finally, sNKG2DLs in patients' plasma down-regulated NKG2D on NK and CD8 + T cells and impaired NKG2D-mediated cytotoxicity of NK cells. Thus, NKG2D detuning by sNKG2DLs may promote HIV-1 immune evasion and compromise host resistance to opportunistic infections, but HAART and MMPI have the potential to avoid such immune dysfunction.

Original languageEnglish
Pages (from-to)2440-2450
Number of pages11
JournalFASEB Journal
Volume27
Issue number6
DOIs
Publication statusPublished - Jun 2013

Fingerprint

T-cells
Cytotoxicity
Natural Killer Cells
Natural Killer T-Cells
HIV Infections
HIV-1
Highly Active Antiretroviral Therapy
Ligands
Matrix Metalloproteinase Inhibitors
T-Lymphocytes
HIV
Immune Evasion
Immunologic Monitoring
Jurkat Cells
Opportunistic Infections
Major Histocompatibility Complex
Plasmas
Carrier Proteins
Tissue Donors
Cell Line

Keywords

  • Immune evasion
  • MICA/B
  • Shedding
  • ULBP

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Soluble ligands for the NKG2D receptor are released during HIV-1 infection and impair NKG2D expression and cytotoxicity of NK cells. / Matusali, Giulia; Tchidjou, Hyppolite Kuekou; Pontrelli, Giuseppe; Bernardi, Stefania; D'Ettorre, Gabriella; Vullo, Vincenzo; Buonomini, Anna Rita; Andreoni, Massimo; Santoni, Angela; Cerboni, Cristina; Doria, Margherita.

In: FASEB Journal, Vol. 27, No. 6, 06.2013, p. 2440-2450.

Research output: Contribution to journalArticle

Matusali, Giulia ; Tchidjou, Hyppolite Kuekou ; Pontrelli, Giuseppe ; Bernardi, Stefania ; D'Ettorre, Gabriella ; Vullo, Vincenzo ; Buonomini, Anna Rita ; Andreoni, Massimo ; Santoni, Angela ; Cerboni, Cristina ; Doria, Margherita. / Soluble ligands for the NKG2D receptor are released during HIV-1 infection and impair NKG2D expression and cytotoxicity of NK cells. In: FASEB Journal. 2013 ; Vol. 27, No. 6. pp. 2440-2450.
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AU - Tchidjou, Hyppolite Kuekou

AU - Pontrelli, Giuseppe

AU - Bernardi, Stefania

AU - D'Ettorre, Gabriella

AU - Vullo, Vincenzo

AU - Buonomini, Anna Rita

AU - Andreoni, Massimo

AU - Santoni, Angela

AU - Cerboni, Cristina

AU - Doria, Margherita

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AB - In humans, the interaction of the natural killer group 2 member D (NKG2D)-activating receptor on natural killer (NK) and CD8+ T cells with its major histocompatibility complex class I-related chain (MIC) and UL16 binding protein (ULBP) ligands (NKG2DLs) promotes recognition and elimination of stressed cells, such as tumor or infected cells. Here, we investigated the capacity of HIV-1 to modulate NKG2DL expression and escape NGK2D-mediated immunosurveillance. In CD4+ T lymphocytes, both cell surface expression and release of MICA, MICB, and ULBP2 were up-regulated >2-fold by HIV-1 infection. In HIV-infected CD4+ T lymphocytes or Jurkat T-cell lines, increased shedding of soluble NKG2DLs (sNKG2DLs) was impaired by a matrix metalloproteinase inhibitor (MMPI). Moreover, naive HIV+ patients displayed increased plasma sMICA and sULBP2 levels and reduced NKG2D expression on NK and CD8+ T cells compared to patients receiving highly active antiretroviral therapy (HAART) or healthy donors. In individual patients, HAART uptake resulted in the drop of sNKG2DL and recovery of NKG2D expression. Finally, sNKG2DLs in patients' plasma down-regulated NKG2D on NK and CD8 + T cells and impaired NKG2D-mediated cytotoxicity of NK cells. Thus, NKG2D detuning by sNKG2DLs may promote HIV-1 immune evasion and compromise host resistance to opportunistic infections, but HAART and MMPI have the potential to avoid such immune dysfunction.

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