Natural Killer Cells and Cytotoxic T Cells: Complementary Partners against Microorganisms and Cancer

Abstract

Natural killer (NK) cells and cytotoxic T (CD8⁺) cells are two of the most important types of immune cells in our body, protecting it from deadly invaders. While the NK cell is part of the innate immune system, the CD8⁺ cell is one of the major components of adaptive immunity. Still, these two very different types of cells share the most important function of destroying pathogen-infected and tumorous cells by releasing cytotoxic granules that promote proteolytic cleavage of harmful cells, leading to apoptosis. In this review, we look not only at NK and CD8⁺ T cells but also pay particular attention to their different subpopulations, the immune defenders that include the CD56⁺CD16^dim, CD56^dimCD16⁺, CD57⁺, and CD57⁺CD16⁺ NK cells, the NKT, CD57⁺CD8⁺, and KIR⁺CD8⁺ T cells, and ILCs. We examine all these cells in relation to their role in the protection of the body against different microorganisms and cancer, with an emphasis on their mechanisms and their clinical importance. Overall, close collaboration between NK cells and CD8⁺ T cells may play an important role in immune function and disease pathogenesis. The knowledge of how these immune cells interact in defending the body against pathogens and cancers may help us find ways to optimize their defensive and healing capabilities with methods that can be clinically applied.

Keywords: NK subpopulation; adaptive immunity; cytotoxic T cell; granules; immunosenescence; innate immunity; microorganism; natural killer cell.

Figure 1

Induction of long COVID, ME/CFS, and autoimmunity due to viral infection/reactivation in the absence of successful regulation by KIR⁺CD8⁺ regulatory T cells.

Figure 2

Seven major cells that protect our body against pathogens, cancers, and neo-antigens. The identifying cluster differentiation (CD) markers for each specific cell type are outlined in red boxes.

Figure 3

How NK and cytotoxic T-cell subpopulations respond during the early and late phases of infection.

Figure 4

NK granular release. (1) The activated NK cell releases the granules (blue molecules). (2) The granules release perforin (yellow molecules), which blasts holes in the surface membrane of the viral-infected or cancer cell. (3) The granules then release the granulysin (green molecules), which enters the cell through the holes made by the perforin and induces apoptosis or cell death.

Figure 5

The multiple interactions of NK cells with other cells of the immune system. NK cells perform various functions and roles that require them to interact with different cells in different ways, from shaping immune responses through the production of cytokines, to the outright killing or destroying of infected cells or cancer cells through the release of granules.

Figure 6

Why NK cells kill viral-infected cells and tumor cells, but not healthy cells. (1) Two different receptors on NK cells and the ligands on healthy cells ensure that NK cells do not attack normal cells. (2) Healthy cells express a significant level of MHC Class I, which engages with the inhibitory receptor. Because the ligand for NK cells does not engage the activating receptor, the NK does not kill the healthy cell. (3) In viral-infected and cancer cells, MHC Class I is significantly reduced, preventing the inhibitory receptor from engaging with it. But the activating receptor on the NK cell binds strongly to the ligand for NK cells on the viral-infected/cancer cell, causing the release of destructive granules from the NK cell, resulting in the killing of the viral-infected cell or tumor cell (see also Figure 3 and Figure 4).

Figure 7

The caspase-mediated pathway to apoptosis. The binding of the CD95 Fas ligand (FasL) from the NK cell to the Fas on the tumor cell initiates a chain of events that activates Caspase 8, ultimately leading to the death or apoptosis of the cancer cell.