Preprint
Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory
Registro en:
TONNERRE, Pierre et al. Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory. bioRxiv preprint, p. 1-49, Apr. 2021.
10.1101/2021.04.03.437705
Autor
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.
Resumen
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.