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Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral 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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Figure 1: Memory and exhausted CD8+ T cells express multiple inhibitory receptors.
Figure 2: Four types of LCMV infection.
Figure 3: Influence of the severity of infection on the expression of inhibitory receptors and CD8+ T cell function.
Figure 4: Concurrent expression of multiple inhibitory receptors increases with viral load and is associated with lower functionality.
Figure 5: Blockade of PD-L1 and LAG-3 during chronic LCMV infection enhances antiviral CD8+ T cell responses.
Figure 6: Improved function of exhausted CD8+ T cells after dual blockade of LAG-3 and PD-L1.
Figure 7: Greater viral control after dual blockade of PD-L1 and LAG-3.

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Acknowledgements

We thank E. Long, V. Kumar and S. Reiner for comments and suggestions, and B. Laidlaw for critically reading the manuscript. Supported by the National Institute of Allergy and Infectious Diseases (AI071309 to E.J.W and HHSN26620050030C to E.J.W. and G.J.F.) and the Bill and Melinda Gates Foundation Grand Challenge in Global Health (G.J.F. and E.J.W.).

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S.D.B. and E.J.W. designed the experiments; S.D.B. did the experiments with assistance from H.S., T.Z. and A.P.; S.D.B. and E.J.W. analyzed results with input from W.N.H. and M.R.B. and wrote the manuscript; and C.J.W., G.J.F. and D.A.A.V. provided crucial reagents and intellectual input.

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Correspondence to E John Wherry.

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G.J.F. has patents on the PD-1 pathway and receives royalties from those patents.

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Blackburn, S., Shin, H., Haining, W. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 10, 29–37 (2009). https://doi.org/10.1038/ni.1679

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