T Cells Are A Heterogeneous Population of Cytotoxic T Cells and T-Helper Cells

All T cells express a T-cell antigen receptor (TCR), CD28 and related molecules, and either CD4 (helper cells) or CD8 (cytotoxic cells). TCR specifically binds to antigenic peptides that are presented by APCs. Based on discrete functions of T cells, these cells are subdivided into two major types: (1) helper cells and (2) cytotoxic cells. T-helper (Th) cells secrete proteins called cytokines that act on other immune cells to provide help and coordinate immune responses. The cells express the CD4 receptor. These cells express the CD8 molecule (but not CD4) and have granules that are rich in serine esterase granzymes. Cytotoxic T cells also have perforins and lymphotoxins that are important in initiating cytotoxicity and killing infected and abnormal cells.

T-helper cells, based on the predominant cytokines secreted, are further divided into three major types: Th-1, Th-2, and Th-17. Th-1 cells predominantly secrete interleukin-2 (IL-2), interferon-gamma (IFN-γ), and tumor necrosis factor beta (TNF-β). Th-1 immunity is critical for defense against intracellular pathogens (viral, bacterial, or protozoal) and certain types of tumors. Th-1 cells are preferentially generated when naïve CD4⁺ cells are exposed to IL-12, a cytokine from antigen-presenting cells (Figure 55-2). Failure to generate Th-1 cells creates susceptibility to these infections. Abnormal activation of Th-1 cells can result in a wide variety of inflammatory conditions, including autoimmune states.

Activation of naïve CD4⁺ cells with interleukin-4 (IL-4) leads to differentiation into Th-2 cells (see Figure 55-2). Th-2 cells predominantly secrete IL-4, interleukin-6 (IL-6), interleukin-5 (IL-5), and interleukin-10 (IL-10). Generation of Th-2 cells is essential for defense against extracellular pathogens, neutralization of toxins and viruses in body fluids, and activation of other cells of the immune system. Abnormal regulation of Th-2 cells leads to allergies.

Activation of CD4 T-helper cells with IL-6 and transforming growth factor beta (TGFβ) induces the differentiation of Th-17 cells, which secrete a powerful pro-inflammatory cytokine, interleukin-17 (IL-17; see Figure 55-2). This cytokine is now recognized as an important mediator of inflammatory and autoimmune diseases. IL-17 acts on target cells to activate key signaling molecules to promote inflammation through several mechanisms including: (1) recruiting inflammatory cells (e.g., neutrophils, monocytes, and macrophages) to the site of inflammation; (2) acting on target cells (e.g., fibroblasts, epithelial cells) to stimulate a broad range of strong pro-inflammatory molecules (e.g., IL-6, monocyte chemotactic protein 1, nitric oxide); and (3) synergizing with TLR ligands. Although IL-17 is protective in infection, overproduction of IL-17 is known to aggravate certain disease conditions (e.g., autoimmune diseases such as systemic lupus erythematosus and multiple sclerosis).

Exposure of CD4 naïve cells to TGFβ alone (e.g., in the absence of IL-6) will drive the differentiation to T regulatory cells (Treg cells; see Figure 55-2). Treg cells are a population of T cells which act as powerful suppressors of the T cell-mediated immune response and of self-reactive T cells in autoimmune diseases. Tregs utlilize a broad range of suppressive mechanisms which include release of immunosuppressive cytokines TGFβ and IL-10, and cell-cell contact. IL-10 and TGFβ secreted by Tregs are critical for dampening immune responses in allergy, burns, pregnancy, cancer, viral diseases, and autoimmune diseases. Treg cells can inhibit and downregulate all three (Th-1, Th-2, and Th-17) subsets of CD4 cells (see Figure 55-2). Dysregulation of Treg cells can lead to massive inflammatory diseases, while excessive numbers or functions of Tregs can lead to dampening of immune responses that lead to severe infections. Therefore, physiologically, Treg cells must be finely balanced to maintain immune health status.

Thus it is clear that the immune system must initiate the correct type of immune response to maintain homeostasis and defend the host appropriately against the invasion of different types of pathogens.

MHC Class I Antigens of Infected Nucleated Cells Play A Major Role in Activating Cytotoxic T Cells

Cytotoxic killing of intracellularly infected, cancer, or autoreactive cells is an essential step in survival by containing infected cells or the spread of deleterious cells. For example, a viral infection of any cell in the body yields to viral replication within the cell, and some of these viral peptides will physically bind to intracellular MHC class I antigens (Figure 55-3). This viral peptide–MHC class I complex is carried to the surface and displayed as an altered MHC class I molecule. TCR molecules of effector CD8⁺ cytotoxic T cells will recognize the class I molecule–peptide complex to initiate cytotoxicity by at least four different, but complementary, mechanisms. First, contact of a cytotoxic CD8⁺ cell with an infected cell that is displaying a MHC class I–peptide complex will immediately result in cytoplasmic reorganization within the CD8⁺ cell. This includes the alignment of granules and Golgi apparatus at the site of contact. Perforins in the cytotoxic cells polymerize to form tiny injectable tubes referred to as membrane attack complexes (MACs) that “drill” holes into the target cells. Granzymes are passed from the cytotoxic cells into the target cells through these perforin tubes to initiate apoptosis.