Human T Cell Memory: A Dynamic View

Abstract

Long-term T cell-mediated protection depends upon the formation of a pool of memory cells to protect against future pathogen challenge. In this review we argue that looking at T cell memory from a dynamic viewpoint can help in understanding how memory populations are maintained following pathogen exposure or vaccination. For example, a dynamic view resolves the apparent paradox between the relatively short lifespans of individual memory cells and very long-lived immunological memory by focussing on the persistence of clonal populations, rather than individual cells. Clonal survival is achieved by balancing proliferation, death and differentiation rates within and between identifiable phenotypic pools; such pools correspond broadly to sequential stages in the linear differentiation pathway. Each pool has its own characteristic kinetics, but only when considered as a population; single cells exhibit considerable heterogeneity. In humans, we tend to concentrate on circulating cells, but memory T cells in non-lymphoid tissues and bone marrow are increasingly recognised as critical for immune defence; their kinetics, however, remain largely unexplored. Considering vaccination from this viewpoint shifts the focus from the size of the primary response to the survival of the clone and enables identification of critical system pinch-points and opportunities to improve vaccine efficacy.

Keywords: dynamics; immune memory; kinetics; proliferation; survival; turnover; vaccination; vaccine.

Figure 1

Contrasting ways to store memories—the archive and the story teller. On the left, the Library at Trinity College Dublin (Photo by DAVID ILIFF. License: CC-BY-SA 3.0); the right-hand frame shows a traditional story-teller or Griot, describing, perhaps, what to do on encountering cognate antigen (Photograph: Bushmen, N. R. Farbman for Life magazine, 1946; http://images.google.com/hosted/life/6da6b5c69e36d1ff.html; © Time Inc).

Figure 2

Linear differentiation model for T cells. Model for successive development of stem cell memory (T_SCM), central memory (T_CM), effector memory (T_EM), and terminal effector memory (T_TE) from naive (T_N) T cells. The origin of T_RM is not yet fully clarified (see reference [29]). Adapted from Mahnke et al., 2013 [30] and Youngblood et al., 2015 [31].

Figure 3

Compartment modelling in a vaccine response. Hypothetical simplified model of changes in compartment size following vaccination. The size of the circle represents schematically the relative number of cells of the corresponding phenotype—nave (T_N), central memory (T_CM), effector memory (T_EM), and tissue-resident memory (T_RM).

Figure 4

Kinetic model for T cell differentiation. Model of T cell memory population homeostasis. Circles represent phenotypically defined populations. Each population has a rate of intrinsic proliferation (p), a rate of transition to the next pool (t), and a rate of death (d). At equilibrium, all fluxes are in balance. Pool sizes are determined by the relative values of p, d and t. T_RM and other populations are not shown for simplicity in this diagram.