Differentiation of exhausted CD8+ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory

P Tonnerre, D Wolski, S Subudhi, J Aljabban… - Nature …, 2021 - nature.com
P Tonnerre, D Wolski, S Subudhi, J Aljabban, RC Hoogeveen, M Damasio, HK Drescher
Nature immunology, 2021nature.com
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 …
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.
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