학술논문
Differentiation of exhausted CD8+T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory
Document Type
Article
Author
Tonnerre, Pierre; Wolski, David; Subudhi, Sonu; Aljabban, 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.
Source
Nature Immunology; August 2021, Vol. 22 Issue: 8 p1030-1041, 12p
Subject
Language
ISSN
15292908; 15292916
Abstract
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. Here we confirmed pervasive phenotypic, functional and transcriptional differences between memory and exhausted antigen-specific CD8+T cells in human hepatitis C virus (HCV) infection before and after treatment. After viral cure, phenotypic changes in clonally stable exhausted T cell populations suggested differentiation toward 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 less time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved HCV infection. Thus, the duration of T cell stimulation impacts exhaustion recovery, with antigen removal after long-term exhaustion being insufficient for the development of functional T cell memory.