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Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection

Nature Immunology volume 10, pages 2937 (2009) | Download Citation


T cell exhaustion often occurs during chronic infection and prevents optimal viral control. The molecular pathways involved in T cell exhaustion remain poorly understood. Here we show that exhausted CD8+ T cells are subject to complex layers of negative regulation resulting from the coexpression of multiple inhibitory receptors. Exhausted CD8+ T cells expressed up to seven inhibitory receptors. Coexpression of multiple distinct inhibitory receptors was associated with greater T cell exhaustion and more severe infection. Regulation of T cell exhaustion by various inhibitory pathways was nonredundant, as blockade of the T cell inhibitory receptors PD-1 and LAG-3 simultaneously and synergistically improved T cell responses and diminished viral load in vivo. Thus, CD8+ T cell responses during chronic viral infections are regulated by complex patterns of coexpressed inhibitory receptors.

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We thank E. Long, V. Kumar and S. Reiner for comments and suggestions, and B. Laidlaw for critically reading the manuscript. Supported by the National Institute of Allergy and Infectious Diseases (AI071309 to E.J.W and HHSN26620050030C to E.J.W. and G.J.F.) and the Bill and Melinda Gates Foundation Grand Challenge in Global Health (G.J.F. and E.J.W.).

Author information


  1. Immunology Program and Wistar Vaccine Center, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.

    • Shawn D Blackburn
    • , Haina Shin
    • , Tao Zou
    • , Antonio Polley
    •  & E John Wherry
  2. Department of Hematology/Oncology, Children's Hospital, Boston, Massachusetts, USA.

    • W Nicholas Haining
  3. Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.

    • W Nicholas Haining
  4. Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.

    • Gordon J Freeman
  5. Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

    • Michael R Betts
  6. Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

    • Creg J Workman
    •  & Dario A A Vignali


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S.D.B. and E.J.W. designed the experiments; S.D.B. did the experiments with assistance from H.S., T.Z. and A.P.; S.D.B. and E.J.W. analyzed results with input from W.N.H. and M.R.B. and wrote the manuscript; and C.J.W., G.J.F. and D.A.A.V. provided crucial reagents and intellectual input.

Competing interests

G.J.F. has patents on the PD-1 pathway and receives royalties from those patents.

Corresponding author

Correspondence to E John Wherry.

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