RT Journal Article
SR Electronic
T1 Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.04.03.437705
DO 10.1101/2021.04.03.437705
A1 Pierre Tonnerre
A1 David Wolski
A1 Sonu Subudhi
A1 Jihad Al-Jabban
A1 Ruben C. Hoogeveen
A1 Marcos Damasio
A1 Hannah K. Drescher
A1 Lea M. Bartsch
A1 Damien C. Tully
A1 Debattama R. Sen
A1 David J. Bean
A1 Joelle Brown
A1 Almudena Torres-Cornejo
A1 Maxwell Robidoux
A1 Daniel Kvistad
A1 Nadia Alatrakchi
A1 Ang Cui
A1 David Lieb
A1 James A. Cheney
A1 Jenna Gustafson
A1 Lia L Lewis-Ximenez
A1 Lucile Massenet-Regad
A1 Thomas Eisenhaure
A1 Jasneet Aneja
A1 W. Nicholas Haining
A1 Raymond T. Chung
A1 Nir Hacohen
A1 Todd M. Allen
A1 Arthur Y. Kim
A1 Georg M. Lauer
YR 2021
UL http://biorxiv.org/content/early/2021/04/04/2021.04.03.437705.abstract
AB 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.Competing Interest StatementAbbVie sponsored the clinical trial (NCT02476617) and provided input to the trial design and clinical and biological sample collection schedule. W.N.H. is an employee of Merck and Company and holds equity in Tango Therapeutics and Arsenal Biosciences. All other authors declare no competing interests.