Cytokines In Immunity To Infection

Apart from cytotoxic effector function, T cells play another important regulatory role in immunity to infection through the production of cytokines. These affect the activity of a wide range of cells, enhancing the function of some, inhibiting that of others. In particular, lymphokines activate macrophages; cells which play a vital role in host defence against many bacteria, fungi and parasites.

As described earlier, many extracellular bacteria are most effectively controlled by specific antibody production. The latter requires the activation of specific T cells that produce cytokines to promote the proliferation and differentiation of B cells and the switching of antibody class. We have previously discussed the effect of different cytokines on the proliferation of Th and Th2 subsets and there is clear evidence that recovery from certain infections is dependent upon the predominance of one of these subsets and the cytokines they produce, e.g. trypanosomiasis and Th2 cells.

Intracellular infections are principally controlled by Th responses. Products from bacteria and/or parasites stimulate IL-12 production (principally from macrophages) and thus, these early interactions initiate a Th1 response. In vivo, IL-12 induces IFNg production, enhances NK cell activation, and promotes protective responses.

The immune response to viral infections may be divided into separate stages, each being associated with a particular pattern of cytokine secretion. In the first stage, IFNa/b production causes the activation of NK cells (Table 6.7). This may be accompanied by IFNg and/or IL-12 production.

The replication of viruses inside cells results in the production of a specialised cellular protein, interferon, which acts to limit the infection. Although most viruses stimulate interferon production, the amount produced depends on the virus. DNA viruses are poorer stimulators of interferon than RNA viruses (which include the paramyxoviruses, e.g. Sendai virus), which are the best. After production, interferon diffuses away from the site of infection, inducing an anti-viral state in neighbouring cells and preventing the synthesis of viral nucleic acids. These effects collectively inhibit growth and spread of the virus.

Interferon production is one of the earliest host responses to viral infection, which commences within the first 24 hours after invasion. Different types of interferon are produced depending upon the site of infection and the cells affected. If fibroblasts are among the infected cells, interferon-b is produced. If the site of infection is populated by leukocytes or if the virus spreads to the blood or lymphoid tissue, interferon-a is produced. Finally, if T lymphocytes are activated by antigen at the site of infection, interferon-y is also produced. The combined action of these three interferons slows the infection down with interferons-a and -b exerting direct anti-viral effects and interferon-y mainly enhancing the immune response (it activates macrophages, augments the activity of NK and Tcyt cells and increases the expression of MHC molecules on many cells).

Interferon is only effective for a short time and hence plays a major role in acute, short-term infections such as the common cold and influenza. It has no effect on viral multiplication in cells that are already infected.

The latter has potent immunoregulatory functions, which include augmentation of the activity of Tcyt and NK cells and enhancing the production of IFNg, which has been shown to enhance Th responses whilst inhibiting Th2 responses.

Table 6.7 Characteristics of interferon alpha and beta

Characteristic

Type

Description

Types of interferon

Major cellular sources

Effects

Cross-reactivity

Human interferons comprise: IFNaI (19.2-19.7 kDa), IFNaII (20.1kDa), IFNb (20 kDa)

Murine interferons comprise: IFNa(19.1 kDa), IFNb (19.7 kDa)

IFNa Lymphocytes, monocytes and macrophages

IFNb Fibroblasts and some epithelial cells

IFN a Confers resistance to viruses on target cells, inhibits cell proliferation and regulates expression of MHC Class I antigens IFNb Related to IFNa; shares the same receptor and has very similar biological activities

IFN a IFN a shows about 40% homology between humans and mice and there is some species restriction depending on the particular molecule

IFNb IFNb shows about 48% homology in humans and mice; there is NO

cross-species reactivity

Following the initial response to virus infection, T cells are activated resulting in the expansion of CD8 + T cells and the production of antigen-specific, Class I restricted, Tcyt cells. The cytokines produced during this stage of the response include IL-2, IFNg, IL-4 and/or IL-10, as well as biologically active TGFb (Table 6.8). The role of these cytokines in the generation of active Tcyt cells is unclear since studies using IFNg and IL-2-deficient mice indicate that these factors are not essential in this process. At this stage of the infection, it is interesting to note that NK cell activity is inhibited but B cells are stimulated. The latter appear to be vital in the final stages of the immune response to viral infection. Although resolution of infection appears to be dependent on Tcyt cell activity, termination of the immune response is related to antigen clearance, which is mediated by antibody.

The family of transforming growth factors known as beta are a group of proteins, which mediate diverse effects on a variety of cells such that TGFfi can be both immunosuppressive or immunoenhancing depending on the cell type involved. TGFfi inhibits the activation of macrophages by IFNy and prevents the synthesis of reactive oxygen and nitrogen metabolites. Thus, the local production of this cytokine during intracellular infections, e.g. with bacteria or parasites, may be pathogenetic. In addition, TGFfi inhibits IL-2-dependent cytotoxic T lymphocyte responses but not by interfering with the binding of IL-2 to its receptor.

In recent years, another group of cytokines - the chemokines - have been shown to play an important role in the regulation of immunity to infection.

Table 6.8 Characteristics of the transforming growth factors

Characteristic

Description

Molecular weight

44.3 kDa (humanTGF//1); 47.8 kDa (humanTGF/2); 47.3 kDa (humanTGF/3)

Major cellular sources

Platelets containTGF/1and /2. Most nucleated cell types and many tumours expressTGF/1, 2, 3 or combinations thereof

Effects

Involved in tissue remodelling, wound repair, development and haemato-poiesis. Inhibits cell growth. Switch factor for IgA

Cross-reactivity

TGF/ species show greater than 98% homology in humans and mice

CXCR4 and CCR5 have been shown to be key co-receptors for HIV infection and their ligands can inhibit this infection.

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