Understanding Subset Diversity in T Cell Memory

Abstract

Considerable advances have been made in recent years in understanding the generation and function of memory T cells. Memory T cells are typically parsed into discreet subsets based on phenotypic definitions that connote distinct roles in immunity. Here we consider new developments in the field and focus on how emerging differences between memory cells with respect to their trafficking, metabolism, epigenetic regulation, and longevity may fail to fit into small groups of "memory subsets." Rather, the properties of individual memory T cells fall on a continuum within each of these and other parameters. We discuss how this continuum influences the way that the efficacy of vaccination is assessed, as well as the suitability of a memory population for protective immunity.

Fig. 1. Traits that distinguish naïve and major memory T cell populations

The bars on the left indicate various characteristics, which can be used to distinguish the T cell subsets listed on the right. The first 4 bars indicate trafficking capabilities and stimulation history of the cells, providing rigid distinctions that can be used to define T cell populations – but note that there is only limited concordance between these traits. The other bars indicate gene expression or phenotypic characteristics, focused on molecules associated with trafficking, tissue retention, and “memory markers” (in mice these would include elevated expression of CD44 and CD11a and reduced expression of CD45RB, while in humans this would include elevated expression of CD45RO and CD11a and reduced expression of CD45RA). Grey shading in these bars indicates where phenotypic/gene expression characteristics fail to clearly correlate with the red and green bars on the left. At the far right are T cell subsets typically associated with these combinations of traits and phenotypic/gene expression characteristics – note that the position of these identifiers is inherently vague, since the typical criteria for defining “subsets” use markers that may not faithfully correlate with the cells’ stimulation history or migration potential. Abbreviations for T cells: Naïve, T_N; Central Memory, T_CM; Effector Memory, T_EM; Tissue-Resident Memory, T_RM; Virtual Memory (also encompassing “Innate” memory), T_VM; Stem Cell Memory, T_SCM; Memory T cells with Naïve Phenotype, T_MNP; Peripheral Memory, T_PM; Long-Lived Effector Cells, T_LLEC; CD45RA+ Effector Memory (defined in humans), T_EMRA; Exhausted T cells, T_EX; T_FH Follicular Helpers). Color coding of the T cell subsets indicates whether they have been primarily described for CD8+ T cells (maroon), CD4+ T cells (gold) or both populations (black).

Fig. 2. Trafficking characteristics is a key feature for resolving memory T cell subpopulations

The schematic indicates the trafficking patterns of several T cell populations. Naïve, and T_CM cells recirculate through blood and SLOs, and enter LNs via HEVs. Some sub-populations of T_EM recirculate from blood to nonlymphoid tissues, and pass through lymphatics and LNs on the way to rejoining the blood supply (recirc T_EM, also referred to as T_PM), while others are confined to recirculating in blood (bloodborne T_EM). T_RM do not recirculate, and are parked within nonlymphoid tissues, SLOs, and local vascular compartments.