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

SD Blackburn, H Shin, WN Haining, T Zou… - Nature …, 2009 - nature.com
SD Blackburn, H Shin, WN Haining, T Zou, CJ Workman, A Polley, MR Betts, GJ Freeman
Nature immunology, 2009nature.com
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 …
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.
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