Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory
Tonnerre, Pierre; Wolski, David; Subudhi, Sonu; Al-Jabban, Jihad; Hoogeveen, Ruben C.; Damasio, Marcos; Drescher, Hannah K.; Bartsch, Lea M.; Tully, Damien C.; Sen, Debattama R.; Bean, David J.; Brown, Joelle; Torres-Cornejo, Almudena; Robidoux, Maxwell; Kvistad, Daniel; Alatrakchi, Nadia; Cui, Ang; Lieb, David; Cheney, James A.; Gustafson, Jenna; Lewis-Ximenez, Lia L.; Massenet-Regad, Lucile; Eisenhaure, Thomas; Aneja, Jasneet; Haining, W. Nicholas; Chung, Raymond T.; Hacohen, Nir; Allen, Todd M.; Kim, Arthur Y.; Lauer, Georg M..
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| PREPRINT-FIOCRUZ | ID: ppf-49718
T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Analysis of antigen-specific CD8+ T cells before and after antigen removal in human hepatitis C virus (HCV) infection confirmed pervasive phenotypic, functional, and transcriptional differences between exhausted and memory CD8+ T cells. After viral cure, we observed broad phenotypic and transcriptional changes in clonally stable exhausted T-cell populations suggesting differentiation towards a memory-like profile. However, functionally, the cells showed little improvement and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for shorter periods of time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved acute HCV infection. Thus, duration of T cell stimulation impacts the ability to recover from exhaustion, as antigen removal after long-term T cell exhaustion is insufficient for the development of key T cell memory characteristics.
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