Temporal and Epigenetic Control of Plasticity and Fate Decision during CD8+ T-Cell Memory Differentiation

Abstract

Immunological memory is a fundamental hallmark of the adaptive immune responses and one of the most relevant aspects of protective immunity. Our understanding of the processes of memory T-cell differentiation and maintenance of long-term immunity is continuously evolving, and recent advances highlight new regulatory networks and chromatin dynamic changes contributing to maintain T-cell identity and impeding the reprogramming of specific T-cell states. Here, the current understanding of the mechanisms that generate the diversity and the heterogeneity of CD8⁺ T-cell subsets will be discussed, focusing on the temporal and epigenetic mechanisms orchestrating the establishment and maintenance of distinct states of T-cell fate determination and functional commitment.

Figure 1.

The distinct phases of CD8⁺ T-cell fate determination are shown. Both transcriptional and epigenetic changes contribute to the terminal commitment of CD8⁺ T cells.

Figure 2.

Different models proposed to explain CD8⁺ T-cell heterogeneity are represented on Waddington's epigenetic landscapes: (A) asymmetric division model, (B) progressive differentiation model, (C) reprogramming model, and (D) multipotent intermediate model.

Figure 2.

Different models proposed to explain CD8⁺ T-cell heterogeneity are represented on Waddington's epigenetic landscapes: (A) asymmetric division model, (B) progressive differentiation model, (C) reprogramming model, and (D) multipotent intermediate model.

Figure 3.

Kinetics of T-cell differentiation and programming. (A) After priming, transcription and epigenetic factor changes determine the activation and silencing of specific gene expression programs, which guide the fate commitment of each CD8⁺ T cell. (B) During the initial steps of differentiation, transcriptional changes guide the transition between states of differentiation. The loss of plasticity and the establishment of epigenetic barriers impede the reprogramming of terminal differentiated effector CD8⁺ T cells.

Figure 4.

Representative active and repressive histone markers and heterochromatin-silencing factors involved in CD8⁺ T-cell fate commitment. (DNMTs) DNA methyltransferases.