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Nat Immunol. 2009 Jan;10(1):29-37. doi: 10.1038/ni.1679. Epub 2008 Nov 30.

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

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


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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