IL-27 promotes the expansion of self-renewing CD8+ T cells in persistent viral infection

J Exp Med. 2019 Aug 5;216(8):1791-1808. doi: 10.1084/jem.20190173. Epub 2019 Jun 4.

Abstract

Chronic infection and cancer are associated with suppressed T cell responses in the presence of cognate antigen. Recent work identified memory-like CXCR5+ TCF1+ CD8+ T cells that sustain T cell responses during persistent infection and proliferate upon anti-PD1 treatment. Approaches to expand these cells are sought. We show that blockade of interferon type 1 (IFN-I) receptor leads to CXCR5+ CD8+ T cell expansion in an IL-27- and STAT1-dependent manner. IFNAR1 blockade promoted accelerated cell division and retention of TCF1 in virus-specific CD8+ T cells. We found that CD8+ T cell-intrinsic IL-27 signaling safeguards the ability of TCF1hi cells to maintain proliferation and avoid terminal differentiation or programmed cell death. Mechanistically, IL-27 endowed rapidly dividing cells with IRF1, a transcription factor that was required for sustained division in a cell-intrinsic manner. These findings reveal that IL-27 opposes IFN-I to uncouple effector differentiation from cell division and suggest that IL-27 signaling could be exploited to augment self-renewing T cells in chronic infections and cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / virology
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Cell Self Renewal / immunology*
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • Immunologic Memory
  • Interferon Regulatory Factor-1 / genetics
  • Interferon Regulatory Factor-1 / metabolism
  • Interleukins / genetics
  • Interleukins / metabolism*
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptor, Interferon alpha-beta / antagonists & inhibitors
  • Receptors, CXCR5 / metabolism
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism
  • Transcriptome

Substances

  • Antibodies, Monoclonal
  • CXCR5 protein, mouse
  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • Ifnar1 protein, mouse
  • Il27 protein, mouse
  • Interferon Regulatory Factor-1
  • Interleukins
  • Irf1 protein, mouse
  • MOPC21 monoclonal antibody
  • Receptors, CXCR5
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Receptor, Interferon alpha-beta