학술논문
Differentiation of exhausted CD8.sup.+ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory
Document Type
Report
Author
Source
Nature Immunology. August 2021, Vol. 22 Issue 8, p1030, 12 p.
Subject
Language
English
ISSN
1529-2908
Abstract
Author(s): Pierre Tonnerre [sup.1] [sup.2] , David Wolski [sup.1] , Sonu Subudhi [sup.1] , Jihad Aljabban [sup.1] , Ruben C. Hoogeveen [sup.1] , Marcos Damasio [sup.1] , Hannah K. Drescher [...]
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.sup.+ 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. Lauer and colleagues examine CD8.sup.+ T cells following cure of human hepatitis C virus (HCV) infection. CD8.sup.+ T cells exposed to chronic HCV-specific activation show durable functional, phenotypic and transcriptional exhaustion that is maintained even after antigen stimulus is removed.
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.sup.+ 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. Lauer and colleagues examine CD8.sup.+ T cells following cure of human hepatitis C virus (HCV) infection. CD8.sup.+ T cells exposed to chronic HCV-specific activation show durable functional, phenotypic and transcriptional exhaustion that is maintained even after antigen stimulus is removed.