Diversity in CD8(+) T cell differentiation

Abstract

CD8(+) T cells are key effector cells of the adaptive immune system, however their activity must be tightly regulated to allow pathogen clearance whilst preventing immunopathology and autoimmunity. In this review, we summarise the diversity of responses that CD8(+) T cells make to antigenic stimulation with a focus on how CD8(+) T cell responses are regulated to achieve different immune outcomes. In particular, we discuss phenotypic diversity during tolerance induction as well as signals that drive effector and memory cell differentiation in response to infection.

Figure 1. A model for generating diverse CD8⁺ T cell fates

(Top portion) Naïve CD8⁺ T cells (brown cell) that encounter antigen on steady-state, tolerogenic DCs (beige cell) proliferate without acquiring effector functions (dark blue cells) in a process dependent on PD-1 and the molecules Egr2, Egr3 (Egr2/3) and Cbl-b. Such tolerised T cells typically up-regulate PD-1 and down-regulate IL-7R as indicated, and either die (black cell) or become anergic (i.e., deficient in TCR signalling as denoted by the red cross). Antigen (Ag) levels control this process, with high Ag levels promoting anergy, and low Ag levels causing deletion. (Lower portion) Immunogenic DCs (red cell), which have encountered pathogen derived products, activate naïve CD8⁺ T cells to form effector cells (cytotoxic granules and production of effector cytokines are indicated). This differentiation process is regulated by molecules such as Id2, Spi-6, Notch, T-bet and eomesodermin (Eomes). These effector cells can adopt multiple cell fates, such as memory precursor cell fates (characterised by IL-7R^hi, KLRG1^lo, T-bet^lo, Blimp-1^int, Spi-2a^hi and Bcl-2^hi expression; bottom left) or short-lived effector cell fates (with IL-7R^lo, KLRG1^hi, T-bet^hi and Blimp-1^hi expression; middle). Such short-lived cells can either become senescent effectors and die by bim-dependent apoptosis, or persist into early memory as short-lived effector memory cells that are CCR7^lo, CD62L^lo and KLRG1^hi. In contrast, memory precursor cells are long-lived and can be CCR7^lo, CD62L^lo, Blimp-1^int effector memory cells (promoted by Id2, Klf2 and Blimp-1), or CCR7^hi, CD62L^hi, Blimp-1^lo central memory cells (driven by Bcl-6). Evidence exists that KLRG1^lo effector cells can also give rise to KLRG1^hi short-lived effector memory cells (denoted by broken arrow and question marks; N. S. Joshi, T. W. Hand and S. M. K., unpublished observations). In some chronic viral infections, PD-1, LAG-3 and IL-10 causes cells to acquire an exhausted phenotype (light blue cell) characterised by high PD-1 and LAG-3 expression and low IL-7R levels. Although the exhausted cell is depicted as sharing a common effector cell precursor with other cell fates, it is currently unclear at what point during effector cell differentiation this fate branches.