Lineage relationship of effector and memory T cells

Abstract

Adaptive immunity is characterized by the ability to form long-lived immunological memory. Upon re-exposure to antigen, memory T cells respond more rapidly and robustly than naïve T cells, providing better clearance of pathogens. Recent reviews have reinforced the text-book view that memory T cells arise from effector cells. Although this notion is teleologically appealing, emerging data are more consistent with a model where naïve cells directly develop into memory cells without transitioning through an effector stage. A clear understanding of the lineage relationships between memory and effector cells has profound implications for the design of vaccines and for the development of effective T cell-based therapies.

Figure 1. The linage relationship of T cell subsets is complicated by the lack of anatomical clues

A) The intestinal crypt-villus unit. Intestinal stem cells reside at the base of the crypt between Paneth cells. As cells proliferate and differentiate into transient amplifying (TA) progenitor cells and mature enterocytes, they move upwards to cover the villus. B) The skin. Epidermal stem cells are located in the bulge region of the hair follicle, the base of the sebaceous gland, and the basal layer of the interfollicular epidermis. As cells proliferate and differentiate into keratinocytes, they move upward to form the stratum spinosus (SS), the granular layer (GL), the stratum lucidum (SL) and the stratum corneum (SC). C) T cells. Following antigen-stimulation, naïve T cells differentiate generating the full diversity T cell subsets. The existence of cells at different developmental stages, all of which are moving within the same anatomical space, does not offer an easy static snapshot that provides clues about their lineage relationships which are still the subject of controversy in the field.

Figure 2. There are two dominant competing models of T cell differentiation

Set of panels shown on the left side depicts the ‘off-on-off’ model, in which all memory T cells are derived from cells that were once effector cells. Shown in the right set of panels is the ‘developmental’ model whereby memory cells arise directly out of naïve precursors without going through an effector stage. These distinct models lead to different predictions, which are explained in detail in the text.

Figure 3. The progressive differentiation CD8⁺ T cell differentiation is largely a linear and unidirectional process

The differentiation of cells proceeding efficiently in mainly one direction has been analogized to a ball rolling down a hill, with the gradual loss of potential. For T cells, this process leads to characteristic changes in cell surface molecules shown. In addition, the model includes observations that cellular differentiation, ie the acquisition of effector functions, is eventually accompanied by senescence. At the same time, there is a loss of ‘stemness’ – the capacity of cells to be multipotent and self-renewing – as well as a diminution in proliferative capacity. Cells move from a metabolism that is based on lipid oxidation and oxidative phosphorylation to one based on glycolysis.