Open AccessDifferentiation of exhausted CD8+ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory
Author(s) -
Pierre Tonnerre,
David Wolski,
Sonu Subudhi,
Jihad Aljabban,
Ruben C. Hoogeveen,
Marcos Damasio,
Hannah K. Drescher,
Lea M. Bartsch,
Damien C. Tully,
Debattama R. Sen,
David J. Bean,
Joelle Brown,
Almudena Torres-Cornejo,
Maxwell Robidoux,
Daniel Kvistad,
Nadia Alatrakchi,
Ang Cui,
David Lieb,
James A. Cheney,
Jenna Gustafson,
Lia Laura Lewis-Ximenez,
Lucile Massenet-Regad,
Thomas Eisenhaure,
Jasneet Aneja,
W. Nicholas Haining,
Raymond T. Chung,
Nir Hacohen,
Todd M. Allen,
Arthur Y. Kim,
Georg M. Lauer
Publication year - 2021
Publication title -
nature immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.074
H-Index - 388
eISSN - 1529-2916
pISSN - 1529-2908
DOI - 10.1038/s41590-021-00982-6
Subject(s) - immunology , cytotoxic t cell , biology , cd8 , chronic infection , antigen , t cell , phenotype , cell , stimulation , virology , immune system , neuroscience , in vitro , gene , genetics
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.