Dendritic Tcell interactions

As T-cells circulate around the body, they pass through the peripheral lymphoid organs, where they transiently adhere to antigen-presenting cells. Contact is made with many thousands of dendritic cells every day. This enables T-cells to 'sample' the many MHC-peptide complexes on the surface of the antigen-presenting cells. Rarely, a circulating T-cell will possess TCRs that conform to the peptide-MHC complex. Binding of the TCR and peptide-MHC complex induces conformational changes in adhesion molecules that increase the interaction between the antigen-presenting cell and the T-cell and keep the T-cell and its progeny in close proximity to the source of their stimulation. T-cell activation is not induced solely by ligation of a TCR, CD4 or CD8 co-receptor with a specific MHC-peptide complex. T-cell proliferation requires a further stimulus from the antigen-presenting cell and this is provided by the antigen-presenting cell surface glycoproteins B7.1 (CD80) and B7.2 (CD86) binding to their receptor (CD28) present on the T-cell. Typically, a TCR binding to an MHC-peptide complex in the absence of co-stimulation leads to T-cell anergy (unresponsive-ness) or apoptosis.

Clonal expansion and differentiation of T-cells into effector cells

Antigen-specific and co-stimulatory interaction between T-cell and antigen-presenting cell triggers T-cell proliferation. After a few days, thousands of T-cell progeny emerge from the peripheral lymphoid organs and localize to the areas of infection or inflammation. Each of these effector T-cells possesses the same antigen specificity as the parent T-cell and they are now available to counteract the stimulating pathogen. These effector T-cells differ from the parent T-cell, because they do not require the co-stimulation provided by antigen-presenting cells; therefore, further encounters by effector T-cells with their specific antigen results in immunological attack. The nature of immunological attack depends on the effector T-cell CD4/CD8 status.

Effector CD8 T-cells

Effector CD8 T-cells (also known as cytotoxic T-cells) play a vital role in counteracting viral infections (Fig. 1.5), which are intracellular and almost completely hidden from the humoral immune response. Effector CD8 T-cells are

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Surface expression of viral peptide + MHC class I molecule

CD8+ T-cell binds to viral peptide + MHC class I molecule

CD8+ T-cell destroys virally infected cell

Virally infected cell destroyed

Fig. 1.5. Schematic representation of virally infected cell by destruction CD8+ effector T-cell.

induced by antigen-presenting cell presentation of MHC class I-peptide complexes to CD8 T-cells. The anti-viral activity of CD8 cytotoxic T-cells depends on the ability of virally infected cells to signal their corrupted state by the cell-surface expression of viral peptide sequences in association with MHC class I molecules. It is these MHC-peptide complexes that are recognized by CD8 TCRs and trigger immunological attack by the CD8 T-cell. It is the interaction between CD8 T-cell and infected cell that enables precise destruction of infected cells and preservation of uninfected cells. After migrating to a site of viral infection, CD8 cytotoxic T-cells sample cell surfaces. If the CD8 T-cell adheres to and identifies an infected cell, the corrupted cell is destroyed by directed localized secretion of cytotoxic enzymes (perforin and granzymes) by the CD8 cell. This effectively neutralizes the viruses infecting the cell. Other anti-viral properties of CD8 cytotoxic T-cells include the secretion of the antiviral cytokine IFN-7 and expression of Fas ligand (CD95L), which induces apoptosis in target cells bearing the Fas (CD95) receptor protein. Clearly, if control of this extremely destructive but precise process is lost and CD8 T-cells start destroying 'self' cells, the consequences are potentially catastrophic. Such a breakdown in control is probably the basis of the immunological destruction of insulin-secreting p cells of the pancreatic islets, resulting in type I (insulin-dependent) diabetes mellitus.

Effector CD4 T-cells

Although CD8 effector T-cells are of major importance in the defence against viruses, they are ineffective in eliminating certain intracellular bacteria, fungi and parasites that are not neutralized by destruction of their host cell. These microorganisms are also resistant to the humoral immune response. These particularly resistant organisms are neutralized by effector CD4 T-cells, which are generated by MHC class II-restricted presentation of peptide by antigen-presenting cells. Effector CD4 T-cells are more commonly known as T-helper (Th) cells.

Th-cells and macrophages (Stout and Bottomly, 1989)

Macrophages usually destroy phagocytosed microorganisms. However, certain pathogens (e.g. Mycobacteria, Leishmania and Pneumocystis) have evolved mechanisms that resist macrophage destruction. After directed migration of Th-cells to the site of infection, Th-cells sample the peptide-MHC class II surface-molecular repertoire of adjacent cells. Macrophage activation occurs if the surface-expressed peptide-MHC class II is recognized by a Th-cell possessing the complementary TCR. This macrophage-Th-cell interaction alone is insufficient to activate the macrophage, and two further signals are required (Fig. 1.6). The first is IFN-7; this is usually secreted by the engaged Th-cell, but other sources of IFN-7 are also important, e.g. CD8 cytotoxic T-cells. The second signal sensitizes the macrophage to IFN-7 and this second signal can also be provided by Th-cells, which express surface CD40 ligand molecules; these interact with macrophage surface CD40 molecules.

Infected macrophage expressing MHC class II-restricted peptide

Th-cell recognizes peptide-MHC class I complex

Th-cell activates macrophage

Activated macrophage destroys microorganism, some bystander tissue damage

Fig. 1.6. Schematic representation of Th-cell activation of macrophage infected with resistant microorganism.

Activated macrophage destroys microorganism, some bystander tissue damage

Fig. 1.6. Schematic representation of Th-cell activation of macrophage infected with resistant microorganism.

Clearly, Th-cells are extremely potent antigen-specific macrophage activators, because they provide both the IFN-7 and the CD40 signals required for macrophage activation. Th-cell-induced activation greatly enhances macrophage antimicrobial and antigen-presenting capacity. The increased antimicrobial capacity of activated macrophages in part derives from the following:

  1. Increased efficiency of lysosome fusion with microbe-containing phago-somes.
  2. Increased synthesis of antimicrobial proteases and peptides, such as defensins.
  3. Induction of the respiratory burst produces extremely microbiocidal products, such as the superoxide anion (O^), singlet oxygen (1O2), the hydroxyl radical (OH), and hydrogen peroxide (H2O2).
  4. Production of the reactive nitrogen metabolite nitric oxide (NO) is increased by activation of the enzyme inducible NO synthase (iNOS).

Macrophage activation is associated with the release of anti-microbial mediators that are not only toxic to microorganisms but also extremely toxic to host cells, resulting in host tissue damage. If macrophages constitutively remained in this activated state, massive tissue damage would occur. Therefore, macrophage activation is tightly regulated and extremely pathogen-specific. The control and antigen specificity of macrophage activation is provided by antigen-specific Th-cells. Thus the price paid by the host, in terms of tissue damage, in order to destroy these difficult invading intracellular organisms is minimized.

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