Evolutionary pressures resulted in the development of efficient cell-based methods to kill infected or abnormal cells. CD8, CD4, and natural killer (NK) cells (see Chapter 21) are the major effector cells involved in this cell-mediated response. Cytotoxic CD8 and CD4 cells are antigen specific and genetically restricted. In contrast, NK cells can kill a wide variety of target cells without the need for antigen presentation on class I proteins. Lysis of target cells follows cell-to-cell contact between effector and target cells. Other cells such as monocytes and eosinophils also have the ability to kill cells. However, killing by these cells is facilitated by the secretion of cytolytic cytokines or proteins and does not require cell-to-cell contact or antigen presentation by class I or II molecules.

CD8 Cytotoxic Cells

Cytotoxic T cells are activated by dendritic cells that express antigen-loaded class I molecules. Dendritic cells ingest intact cells (cross-priming) or free antigens. After processing, antigens are presented in the context of class I or class II molecules. Three signals are required for T cell activation and proliferation. The initial signal is provided by the interaction between the CD8 T cell receptor (TCR) and antigen-loaded class I molecules on dendritic cells (Figure 20-1). The second signal is provided by CD28 on T cells interacting with B7-1 on antigen-presenting cells. Proliferation of activated cytotoxic T cells requires the production of interleukin 12 (IL-12) by dendritic cells and autocrine production of IL-2.

CD8 Subpopulations

Two subpopulations of CD8 cells can be differentiated by patterns of cytokine production. For example, CD8Tc1 cells, which provide defense against tumors and viral infections, secrete IL-2, interferon gamma (IFN-γ), and TNF-β. Conversely, CD8Tc2 cells secrete IL-4, IL-5, and IL-10. Within the CD8Tc2 population are two other populations known as Tc2a and Tc2b. The biologic function of CD8Tc2a cells is ill defined. They are strongly cytotoxic and may play a role in neurologic and autoimmune diseases. CD8Tc2b cells are only weakly cytotoxic but secrete proteins that prevent intracellular viral replication. In organs that are critical to survival (e.g., brain), CD8Tc2b cells resolve viral infections without destroying the organs.

CD4 Cytotoxic Cells

One of the basic paradigms of immunology is that CD4 cells are involved in inflammatory reactions or antibody production and that CD8 cells are cytotoxic cells. This paradigm has been challenged by recent findings of cytotoxic CD4 cells in peripheral blood. Normally, this population represents less than 2% of the total CD4 population but can expand rapidly during some infections. Although the total numbers of CD4 cells is low in patients with acquired immuno deficiency syndrome (AIDS), 50% of circulating CD4 cells phenotype as cytotoxic CD4 memory cells. These cells have granules containing perforin and granzymes and toxicity is restricted to class II protein–expressing cells. Like CD8 cytotoxic cells, CD4 lysis of infected cells occurs via the perforin, FasL–FasR, and TNF pathways.

The physiologic role of CD4 cytotoxic cells in immunity is not fully delineated. It is tempting to speculate, however, that these cells are involved in the containment of viral infections of B cells and macrophages (Epstein-Barr virus [EBV]–infected B cells or human immunodeficiency virus [HIV]–infected CD4 cells).

Lysis of Target Cells

Target cells can be lysed in three ways: (1) One mechanism involves cytoplasmic granules containing perforin and granzymes. (2) A second mechanism involves the interaction between a Fas ligand (FasL) molecule expressed on cytotoxic T cells and a Fas receptor (FasR) molecule expressed on most target cells. (3) The third mechanism involves ligation of TNF-β receptors (TNFR) expressed on target cells.

Perforin–Granzyme Cytolysis

In perforin–granzyme–target cell lysis, cytotoxic T cells bind antigen-loaded class I antigens on the target cell. The initial reaction is stabilized by CD8, CD2, and leukocyte function–associated antigen 1 (LFA-1) (see Figure 20-1), which creates a small immunologic synapse between the two cells.

Figure 20-1 Some of the ligands involved in the interaction between cytotoxic T lymphocytes (CTLs) and their targets. (*ICAM-1*, intercellular adhesion molecule-1; *TCR*, T cell receptor; *LFA-3*, leukocyte functional antigen-1.) (From Roitt I, Brostoff J, Male D, et al: Immunology, ed 7, Philadelphia, 2006, Mosby.)

Following synapse formation, microtubules within the T cell align themselves so that unidirectional movement of intracellular granules occurs toward the synapse.

Granules containing granulysin, perforin, granzymes, and cathepsin C move along the microtubules and fuse with the target cell plasma membrane (Figure 20-2).