The smallest unit: effector and memory CD8(+) T cell differentiation on the single cell level

Abstract

CD8(+) T cell immune responses provide immediate protection against primary infection and durable memory capable of rapidly fighting off re-infection. Immediate protection and lasting memory are implemented by phenotypically and functionally distinct T cell subsets. While it is now widely accepted that these diverge from a common source of naïve T cells (T(n)), the developmental relation and succession of effector and memory T cell subsets is still under intense debate. Recently, a distinct memory T cell subset has been suggested to possess stem cell-like features, sparking the hope to harness its capacity for self-renewal and diversification for successful therapy of chronic infections or malignant diseases. In this review we highlight current developmental models of memory generation, T cell subset diversification and T cell stemness. We discuss the importance of single cell monitoring techniques for adequately mapping these developmental processes and take a brief look at signaling components active in the putative stem cell-like memory T cell compartment.

Keywords: T memory stem cell; memory ontogeny; single cell fate mapping; single cell resolution; subset diversification.

Figure 1

Memory CD8+ T cells share traits of both the naïve and effector compartment. Like T_n, T_cm express lymph node homing molecule L-Selectin (CD62L) and IL7 receptor α chain (CD127) conveying recirculation capacity to secondary lymphoid organs and receptivity to homeostatic cytokine IL7. Like T_ef, T_cm express IL15 receptor β-chain (CD122), and effector cytokine IFNγ. Both molecules are induced by transcription factors Tbet and/or Eomes.

Figure 2

Parallel proliferation hinders delineation of quantitative and qualitative changes in subset abundance. Left panel: In the absence of proliferation or cell death, a change in subset phenotype from A to B can be inferred from the observation. Right panel: In the presence of proliferation (and/or cell death) this inference is not valid.

Figure 3

Single cell resolution required to identify subset segregation. Left panel: Global phenotypic composition changes (from 100% A to 50% A and 50% B) due to emergence of a subset expressing marker B instead of A. Right panel: Global phenotypic composition changes due to global change in expression of A and B.

Figure 4

Alternative proliferative histories of memory T cells. Left panel: Overall primary expansion, contraction and memory maintenance of an epitope-specific T cell population. Upper right panel: The precursors of short-lived and long-lived subsets both contribute equally to primary expansion (“shared proliferative history”). Lower right panel: The precursors of long-lived subsets do not substantially contribute to primary expansion (“distinct proliferative history”).

Figure 5

Single cell fate mapping. Left panel: Continuous monitoring of an individual cell (→). Right panel: Tagging of an individual cell by a heritable marker (X).