NK cell development, homeostasis and function: parallels with CD8⁺ T cells

Abstract

Natural killer (NK) cells survey host tissues for signs of infection, transformation or stress and, true to their name, kill target cells that have become useless or are detrimental to the host. For decades, NK cells have been classified as a component of the innate immune system. However, accumulating evidence in mice and humans suggests that, like the B and T cells of the adaptive immune system, NK cells are educated during development, possess antigen-specific receptors, undergo clonal expansion during infection and generate long-lived memory cells. In this Review, we highlight the many stages that an NK cell progresses through during its remarkable lifetime, discussing similarities and differences with its close relative, the cytotoxic CD8(+) T cell.

Figure 1. Education of developing NK cells and thymocytes

(a) In the bone marrow, developing NK cells interact with MHC class I on stromal and hematopoietic cells via inhibitory receptors, and the number of interactions determine the degree of responsiveness. (b) Developing NK cells that interact with self or viral ligands via activating receptors will become anergic or hyporesponsive. (c) In the thymus, developing T cells interact with self-peptide/MHC on epithelial and hematopoietic cells via T cell receptors, and affinity or avidity of these interactions determine survival and export to periphery.

Figure 2. Factors that influence the development, homeostasis, and survival of NK cells and T cells

A comparison of lineage specifying and external signals required for the maturation of NK cells and T cells from the common lymphoid progenitor (CLP) are shown. The CLP uses factors such as Notch and RUNX to become immature T cells, whereas ID2 and E4BP4 specify NK cell lineage precursors. Notch, IL-7, and TCR signals dictate “selection” of developing T cells in the thymus, while IL-15 and inhibitory receptor signals promote proliferation and “education” of developing NK cells in the bone marrow. Factors that influence the survival and function of T and NK cells during antigen-driven versus homeostatic proliferation are shown, including cytokine signals, cell surface receptor signals, and various other unknown signals.

Figure 3. Specific and nonspecific response of NK cells and CD8⁺ T cells during infection

(a) During viral infection, NK cells and CD8⁺ T cells mount “specific” responses upon antigen receptor triggering. TCR-MHC interactions, costimulation, and pro-inflammatory cytokines such as interleukin-12 (IL-12) and type I interferons (IFNs) are the three signals thought to promote the activation and clonal expansion of naïve CD8⁺ T cells. Similarly, resting NK cells receive signals via activating receptors and inflammatory cytokine receptors; it is unclear whether costimulatory molecules play an important role in NK cell activation and expansion. The short and long term functional outcomes are shown. (b) IL-12 and type I IFNs can directly act on memory CD8⁺ T cells and resting NK cells in the absence of antigen receptor triggering, leading to “nonspecific” or “bystander” responses. The short and long term functional outcomes are shown.

Figure 4. Comparing the reactivity of NK cells and CD8⁺ T cells during differentiation

The state of reactivity of resting NK cells and naïve CD8⁺ T cells, activated/effector and memory NK and CD8⁺ T cells is marked by the expression of activation and differentiation markers (KLRG1, CD62L, and Ly6C) and their relative ability to mediate cytotoxicity and secrete effector cytokines is indicated. (T_CM = Central memory T cell, T_EM = Effector memory T cell, lo = low, int = intermediate, hi = high)