Increased expression of programmed death (PD)-1 and its ligand PD-L1 correlates with impaired cell-mediated immunity in high-risk human papillomavirus-related cervical intraepithelial neoplasia

Immunology. 2013 Aug;139(4):513-22. doi: 10.1111/imm.12101.

Abstract

Impaired local cellular immunity contributes to the pathogenesis of persistent high-risk human papillomavirus (HR-HPV) infection and related cervical intraepithelial neoplasia (CIN), but the underlying molecular mechanisms remain unclear. Recently, the programmed death 1/programmed death 1 ligand (PD-1/PD-L1; CD279/CD274) pathway was demonstrated to play a critical role in attenuating T-cell responses and promoting T-cell tolerance during chronic viral infections. In this study, we examined the expression of PD-1 and PD-L1 on cervical T cells and dendritic cells (DCs), respectively, from 40 women who were HR-HPV-negative (-) or HR-HPV-positive (+) with CIN grades 0, I and II-III. We also measured interferon-γ, interleukin-12 (IL-12) and IL-10 in cervical exudates. The most common HPV type was HPV 16, followed by HPV 18, 33, 51 and 58. PD-1 and PD-L1 expression on cervical T cells and DCs, respectively, was associated with HR-HPV positivity and increased in parallel with increasing CIN grade. The opposite pattern was observed for CD80 and CD86 expression on DCs, which decreased in HR-HPV+ patients in parallel with increasing CIN grade. Similarly, reduced levels of the T helper type 1 cytokines interferon-γ and IL-12 and increased levels of the T helper type 2 cytokine IL-10 in cervical exudates correlated with HR-HPV positivity and CIN grade. Our results suggest that up-regulation of the inhibitory PD-1/PD-L1 pathway may negatively regulate cervical cell-mediated immunity to HPV and contribute to the progression of HR-HPV-related CIN. These results may aid in the development of PD-1/PD-L1 pathway-based strategies for immunotherapy of HR-HPV-related CIN.

Keywords: cervical intraepithelial neoplasia; cytokines; human papillomavirus; programmed death-1; programmed death-1 ligand.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • B7-1 Antigen / analysis
  • B7-2 Antigen / analysis
  • B7-H1 Antigen / analysis*
  • Biopsy
  • Case-Control Studies
  • Cervical Intraepithelial Neoplasia / immunology*
  • Cervical Intraepithelial Neoplasia / pathology
  • Cervical Intraepithelial Neoplasia / virology
  • Dendritic Cells / immunology*
  • Dendritic Cells / virology
  • Enzyme-Linked Immunosorbent Assay
  • Exudates and Transudates / immunology
  • Female
  • Flow Cytometry
  • Human Papillomavirus DNA Tests
  • Humans
  • Immunity, Cellular*
  • Interferon-gamma / analysis
  • Interleukin-10 / analysis
  • Interleukin-12 / analysis
  • Neoplasm Staging
  • Papillomaviridae / genetics
  • Papillomaviridae / immunology*
  • Papillomaviridae / pathogenicity
  • Papillomavirus Infections / immunology*
  • Papillomavirus Infections / pathology
  • Papillomavirus Infections / virology
  • Programmed Cell Death 1 Receptor / analysis*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / virology
  • Up-Regulation
  • Uterine Cervical Neoplasms / immunology*
  • Uterine Cervical Neoplasms / pathology
  • Uterine Cervical Neoplasms / virology

Substances

  • B7-1 Antigen
  • B7-2 Antigen
  • B7-H1 Antigen
  • CD274 protein, human
  • CD86 protein, human
  • IFNG protein, human
  • IL10 protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Interleukin-10
  • Interleukin-12
  • Interferon-gamma