Virtual Memory CD8+ T Cells: Origin and Beyond

Abstract

The presence of CD8⁺ T cells with a memory phenotype in nonimmunized mice has been noted for decades, but it was not until about 2 decades ago that they began to be studied in greater depth. Currently called virtual memory CD8⁺ T cells, they consist of a heterogeneous group of cells with memory characteristics, without any previous contact with their specific antigens. These cells were identified in mice, but a few years ago, a cell type with characteristics equivalent to the murine ones was described in healthy humans. In this review, we address the different aspects of its biology mainly developed in murine models and what is currently known about its cellular equivalent in humans.

Keywords: Ag-specific T cells; TIM cells; TVM cells; cancer; human TVM cells; infection.

FIG. 1.

Mechanisms involved in thymic differentiation of T_IM cells. T cell development in the thymus produces many lineages of mature T cells. (A) When the TCR of a single positive CD8 (SP8) cell recognizes an MHC-Ia molecule expressed on TEC, it results in the development of a conventional CD8⁺ T cell. (B) In the context of MHC-Ib expression, SP8 thymocytes can be successfully selected either by TECs or HCs. While SP8 cells selected on TECs have “a more naive” phenotype, the same precursors selected by HCs and exposed to interleukin-4 (IL-4) derived from PLZF-expressing thymocytes convert into T_IM cells. (C) Reduced TCR signaling in SP8 cells in the presence of IL-4 induces Eomes expression and T_IM phenotype acquisition. IL-4 has little effect on Eomes induction when T cells receive a strong TCR signal giving rise mainly to conventional naive SP8 cells. TEC, thymic epithelial cell; HC, hematopoietic cell.

FIG. 2.

Heterogeneous origin and types of cell subsets that compose the T_VM population. T_IM cell development from SP8 thymocytes when they are exposed to IL-4 and MHC-Ib in the thymus. T_VM cells are generated in the periphery from conventional naive cells that emerge from the thymus with a high self-recognition avidity (CD5^hi) and their generation is requisitely dependent on IL-15 signaling. While T_VM cells and T_IM cells were originally distinguished from one another by thymic differential expression of CD44 and CD49d and their dependence on IL-15 versus IL-4, once they emerge into the periphery, the 2 populations are phenotypically indistinguishable. HP memory CD8⁺ T cells (T_HP) are produced by homeostatic mechanisms rather than conventional priming and express markers typical of T_VM cells (high expression of CD44 and CD122 and low expression of CD49d). T_HP can be considered part of the T_VM pool that resides in SLO and is dependent on IL-7 for survival.