Divergent clonal differentiation trajectories of T cell exhaustion.
Nat Immunol
; 23(11): 1614-1627, 2022 11.
Article
em En
| MEDLINE
| ID: mdl-36289450
ABSTRACT
Chronic antigen exposure during viral infection or cancer promotes an exhausted T cell (Tex) state with reduced effector function. However, whether all antigen-specific T cell clones follow the same Tex differentiation trajectory remains unclear. Here, we generate a single-cell multiomic atlas of T cell exhaustion in murine chronic viral infection that redefines Tex phenotypic diversity, including two late-stage Tex subsets with either a terminal exhaustion (Texterm) or a killer cell lectin-like receptor-expressing cytotoxic (TexKLR) phenotype. We use paired single-cell RNA and T cell receptor sequencing to uncover clonal differentiation trajectories of Texterm-biased, TexKLR-biased or divergent clones that acquire both phenotypes. We show that high T cell receptor signaling avidity correlates with Texterm, whereas low avidity correlates with effector-like TexKLR fate. Finally, we identify similar clonal differentiation trajectories in human tumor-infiltrating lymphocytes. These findings reveal clonal heterogeneity in the T cell response to chronic antigen that influences Tex fates and persistence.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Viroses
/
Linfócitos T CD8-Positivos
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article