Acquired transcriptional programming in functional and exhausted virus-specific CD8 T cells

Abstract

Purpose of review: Failure to control viral infections such as HIV results in T-cell receptor (TCR) and inhibitory receptor driven exhaustion of antigen-specific T cells. Persistent signaling by these receptors during chronic viral infection sculpts the transcriptional regulatory programs of virus-specific T cells. The resulting gene expression profile is tailored to temper the potentially damaging effector functions of cytotoxic T cells and adapt them to an antigen-rich and inflammation-rich environment. Here we review recent studies investigating mechanisms of transcriptional regulation of effector, functional memory, and exhausted T-cell functions during acute versus chronic infections.

Recent findings: Patterns of gene expression in virus-specific CD8 T cells are a result of a combination of pro and inhibitory signals from antigen presentation (TCR-mediated) and co-inhibitory receptor ligation (PD-1, 2B4). Further, memory-specific transcriptional regulation of 2B4 expression and signaling impose a self-limiting secondary effector response to a prolonged viral infection. Additionally, differentiation of functional memory CD8 T cells is coupled with acquisition of a repressive epigenetic program for PD-1 expression. However, chronic infection provides a signal that blocks the acquisition of these epigenetic modifications reinforcing the suppression of cytotoxic lymphocyte (CTL) functions in exhausted cells.

Summary: Current findings suggest that the mechanism(s) that delineate functional memory versus exhaustion are coupled with acquisition of transcriptional programs at the effector stage of differentiation, reinforced by cessation or persistence of TCR signaling.

Figure 1

Rolling hill diagram of antigen-mediated transcriptional reprogramming of CD8 T cells during memory differentiation. A) Differentiation of antigen-specific CD8 T cells during primary, secondary, and tertiary acute viral infection. B) Differentiation of antigen-specific CD8 T cells during chronic viral infection versus acute viral infection. The peaks and troughs of the transcriptional landscape of the Y-axis represent the potential to achieve an effector response through the modification of transcriptional programs. The Z-axis (blue arrow) represents the duration of antigen exposure and the lineage commitment of the antigen-specific CD8 T cell. Step 1: Antigen-specific naïve CD8 T cells encounter an antigen-presenting cell and differentiate into cytolytic effector cells. Step 2: During the ~ 10⁵ fold expansion of effector cells a subset of cells commit to a memory fate. Step 3: Following antigen clearance the effector population contracts, with ~5–10% of the population surviving to differentiate into resting memory CD8 T cells, poised to rapidly recall the effector functions. Step 4: Memory CD8 T cells efficiently recall an effector transcriptional profile upon secondary exposure to the antigen or a vaccine boost regimen. Step 5: Secondary effector CD8 T cells undergo less contraction resulting in a greater quantity of self-renewing memory CD8 T cells with a gene expression profile that retains some effector-like transcriptional status. Steps 6 & 7: The resulting memory population generated from a tertiary infection are more effector-like and increased in quantity relative to the primary and secondary memory cells. Step 3’: If the infection persists the antigen-specific CD8 T cells further differentiate with progressive restriction in the ability to recall effector functions and ultimately loss of the virus-specific cells. Step 8: Future efforts will determine if exhausted CD8 T cells can be reprogrammed to obtain the transcriptional regulation of a resting memory CD8 T cell.

Figure 2

Epigenetic modifications at the PD-1 locus are coupled to persistence of antigen. During an acute viral infection (green line) the PD-1 locus in early effector antigen-specific CD8 T cells becomes unmethylated (open lollipops) and the chromatin more accessible relative to naïve and memory CD8 T cells. Functional memory CD8 T cells have reacquire a unique DNA methylation pattern (filled lollipops) relative to their naïve precursors. Exhausted CD8 T cells retain an unmethylated and accessible PD-1 locus during chronic viral infection (red line). Anti-retroviral therapies can reduce viral load, but it remains to be determined if the PD-1 locus becomes remethylated in exhausted virus-specific CD8 T cells.