Hepatitis C virus (HCV) is a chronic, but curable viral infection. To illuminate how exhausted T cells (Tex) respond after the termination of antigen exposure (i.e. disease cure), Tonnerre et al. characterized HCV-specific CD8+ T cells from 20 HCV patients pre- and post-treatment. Relative to CD8+ T cells specific to escaped epitopes (only acute antigen exposure), chronically stimulated Tex cells expressed an activated, exhausted profile that drifted towards memory after cure. However, several Tex transcription factors (e.g., TOX) did not change, and Tex cells failed to improve functionally (cytokine secretion and degranulation) up to three years later.
Contributed by Alex Najibi
This paper was co-submitted along with these 2 others:
Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation
Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans
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.
Author Info: (1) Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. pierre.tonnerre@inserm.fr. (2) Inserm U976, Université de Paris, Insti
Author Info: (1) Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. pierre.tonnerre@inserm.fr. (2) Inserm U976, Université de Paris, Institut de Recherche Saint-Louis, Paris, France. pierre.tonnerre@inserm.fr. (3) Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (4) Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA. (5) Division of Medical Sciences, Harvard Medical School, Boston, MA, USA. (6) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (7) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (8) Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, MA, USA. (9) Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil. (10) Inserm U976, Université de Paris, Institut de Recherche Saint-Louis, Paris, France. (11) Division of Infectious Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (12) Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (13) Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. glauer@mgh.harvard.edu.
