Transcriptional Control of Cell Fate Determination in Antigen-Experienced CD8 T Cells

Abstract

Robust immunity to intracellular infections is mediated by antigen-specific naive CD8 T cells that become activated and differentiate into phenotypically and functionally diverse subsets of effector cells, some of which terminally differentiate and others that give rise to memory cells that provide long-lived protection. This developmental system is an outstanding model with which to elucidate how regulation of chromatin structure and transcriptional control establish gene expression programs that govern cell fate determination, insights from which are likely to be useful for informing the design of immunotherapeutic approaches to engineer durable immunity to infections and tumors. A unifying framework that describes how naive CD8 T cells develop into memory cells is still outstanding. We propose a model that incorporates a common early linear path followed by divergent paths that slowly lose capacity to interconvert and discuss classical and contemporary observations that support these notions, focusing on insights from transcriptional control and chromatin regulation.

Figure 1.

Classical models of memory CD8 T-cell formation during acute infection. (A) Linear differentiation decreasing potential model. The responding population differentiates into effector cells, but some cells accumulate more differentiation signals than others, which drives terminal differentiation. (B) Separate fate with progressive differentiation model. Activated cells initially diverge into distinct effector and memory developmental paths based on early signal strength. Cells in the memory pathway that continue to receive stimulation progressively differentiate and ultimately join the effector pathway. (C) Linear differentiation, stochastic model. Individual naive cells unpredictably commit to a proliferative fate that is coupled to the degree of differentiation. Naive cells first develop into slow cycling central memory precursors (Tcmp), then faster dividing effector memory precursors (Temp), and ultimately highly proliferative terminally differentiated progenies.

Figure 2.

Common linear differentiation, lineage divergence, and progressive restriction. (A) Upon activation, naive cells establish a common linear differentiation program that installs multiple capacities in postactivation cells, such as responsiveness to multiple chemokines, cytokines, and additional costimulatory and coinhibitory receptors, engages migratory capabilities, metabolic capacities, effector functions, and, importantly, comingles expression of regulatory factors that are normally associated with one or another dedicated cell fate. This initial process would facilitate cells to ultimately adopt one of many potential differentiated outcomes later, while being committed to none of them initially, rather serving as progenitors of both terminally differentiated and memory cell progenies. (B) Stochastic transcriptional events result in metastable gene and protein expression states that causes transient lineage bias in some cells among an otherwise homogeneous population (Chang et al. 2008). (C) Cell fate–determining factors reinforce these spontaneous fluctuations, encouraging differentiation along one pathway by enhancing gene expression of the chosen direction, while silencing gene expression that opposes the alternative path at the chromatin level. Cells may interconvert (arrows) until late in their paths.