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

By Shawn D. Blackburn, Haina Shin, W. Nicholas Haining, Tao Zou, C. Workman, Antonio Polley, Michael R. Betts, G. Freeman, D. A. Vignali, E. Wherry. Nature Immunology, 2008

1,666 citations recorded by the source corpus.

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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/a80467cedbe0ede014616b7cd2aff13ead3d6579

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. D. Pardoll
2. E. Wherry
3. Lieping Chen
4. G. Freeman
5. Rafi Ahmed
6. W. Zou
7. Arlene H. Sharpe
8. Ton N. Schumacher

In Oncology

1. Lieping Chen
2. D. Pardoll
3. E. Wherry
4. W. Zou
5. G. Freeman
6. S. Rosenberg
7. Arlene H. Sharpe
8. Rafi Ahmed

Citations in the corpus

• Immune checkpoint blockade: a common denominator approach to cancer therapy (2015, background): “As described above, exhausted or dysfunctional T cells can express multiple immune checkpoint molecules, and LAG-3 and PD-1 are commonly co-expressed in models of chronic infection Blackburn et al., 2009) as well as models of self-antigen recognition (Grosso et al., 2009).”
• Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018, neutral): “J Eur Acad Dermatol Venereol (2016) 30(10):e89–91.”
• The transcription factor NFAT promotes exhaustion of activated CD8+ T cells (2015, positive): “Moreover, antibodies to PD-1 and CTLA-4 have emerged as surprisingly effective agents for cancer immunotherapy (Schietinger and Greenberg, 2014), and individual or combined blockade of TIM3, PD-1, and LAG3 with antagonist antibodies has been shown to reverse exhaustion efficiently in CD8 T cells (Bl”
• PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells (2010, background): “It is induced after T cell activation, and much higher expression of PD-1 is associated with exhausted memory T cells in chronic viral infectio”
• LAG3 (CD223) as a Cancer Immunotherapy Target (2017, background): “Although blockade of LAG3 alone had little effect on the resolution of LCMV, dual LAG3/PDL1 blockade synergized to reduce viral load by reversing exhaustion, thus improving anti-viral CD8+ T cell responses (29).”
• T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment (2013, background): “T cells acquiring multiple inhibitory surface molecules in persistent disease settings such as chronic infection [37,38] and malignancies [30,39 ,40], which effectively prevent T cell activation.”