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

• Published in: Nature immunology Vol. 10; no. 1; pp. 29 - 37
• Main Authors: Shin, Haina, Haining, W Nicholas, Wherry, E John, Betts, Michael R, Polley, Antonio, Blackburn, Shawn D, Vignali, Dario A A, Zou, Tao, Workman, Creg J, Freeman, Gordon J
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.01.2009
• Subjects: Animals; Antigens, CD - metabolism; Antigens, Surface - metabolism; Apoptosis Regulatory Proteins - metabolism; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - virology; Chronic Disease; Disease Models, Animal; Down-Regulation; Immunologic Memory; Lymphocyte Activation; Lymphocytic Choriomeningitis - immunology; Lymphocytic Choriomeningitis - metabolism; Lymphocytic choriomeningitis virus; Mice; Mice, Inbred C57BL; Programmed Cell Death 1 Receptor; Receptors, Immunologic - metabolism
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.1679

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.