Article abstract
Nature Immunology 10, 29 - 37 (2008)
Published online: 30 November 2008 | doi:10.1038/ni.1679
Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection
Shawn D Blackburn1, Haina Shin1, W Nicholas Haining2,3, Tao Zou1, Creg J Workman6, Antonio Polley1, Michael R Betts5, Gordon J Freeman4, Dario A A Vignali6 & E John Wherry1
Abstract
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.
- Immunology Program and Wistar Vaccine Center, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
- Department of Hematology/Oncology, Children's Hospital, Boston, Massachusetts, USA.
- Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.
- Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.
- Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Correspondence to: E John Wherry1 e-mail: jwherry@wistar.org
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