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Phenotypic, Functional and Transcriptional Heterogeneity in T Cell Exhaustion
Book chapter

Phenotypic, Functional and Transcriptional Heterogeneity in T Cell Exhaustion

Ryan Zander and Weiguo Cui
Encyclopedia of Immunobiology, pp.V3:328-V3:351
Academic Press, Second edition
2025
DOI: 10.1016/B978-0-128-24465-4.00278-7

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Abstract

CD8+ T cells responding to chronic viral infection and cancer often display diminished effector function and sustained expression of multiple co-inhibitory receptors, a differentiation process commonly known as T cell exhaustion. Notably, recent evidence indicates that the exhausted CD8+ T cell pool is heterogenous and that, in addition to progenitor and terminally exhausted cell subsets, cells with a robust effector phenotype and cells exhibiting features of both effector and exhausted cells (a hybrid phenotype) develop in settings of persistent antigen exposure. These discoveries have raised several conceptual questions regarding the developmental relationships between these exhausted cell subsets, as well as the molecular mechanisms underlying their differentiation. Here, we discuss recent advances in our understanding of CD8+ T cell heterogeneity in the context of chronic stimulation, including an overview of the unique functions and developmental paths of these distinct populations of CD8+ T cells, as well as the key transcriptional circuits underlying their differentiation. We further highlight how CD4+ T cell “help” and other molecular factors influence this multifaceted differentiation process and discuss how this knowledge may inform the therapeutic targeting of exhausted T cell subsets to improve control over chronic infection and cancer.
 Exhausted T cell differentiation trajectories Exhausted T cell heterogeneity Molecular and transcriptional regulation of exhausted T cell subsets

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