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MICROBIOLOGY AND IMMUNOLOGY MOBILE  -  IMMUNOLOGY CHAPTER THIRTEEN

CYTOKINES AND IMMUNOREGULATION 

I. Overview 

Cytokines are a diverse group of non-antibody proteins that act as mediators between cells. They were initially identified as products of immune cells that act as mediators and regulators of immune processes but many cytokines are now known to be produced by cells other than immune cells and they can have effects on non-immune cells as well. Cytokines are currently being used clinically as biological response modifiers for the treatment of various disorders. The term cytokine is a general term used to describe a large group of proteins but there are other terms that are commonly used to describe particular kinds of cytokines.

These include:

• Monokines, cytokines produced by mononuclear phagocytic cells
• Lymphokines, cytokines produced by activated lymphocytes, especially Th cells
• Interleukins, cytokines that act as mediators between leukocytes

Cytokines are not typically stored as preformed proteins. Rather their synthesis is initiated by gene transcription and their mRNAs are short lived. They are produced as needed in immune responses. Many individual cytokines are produced by many cell types and act on many cell types (i.e., they are pleotropic) and in many cases cytokines have similar actions (i.e., they are redundant).  Redundancy is due to the nature of the cytokine receptors.  Receptors for cytokines are heterodimers (sometimes heterotrimers) that can be grouped into families in which one subunit is common to all members of a given family.  Some examples are shown in Figure 1. Since the subunit common to all members of the family functions in binding cytokine and in signal transduction, a receptor for one cytokine can often respond to another cytokine in the same family.  Thus, an individual lacking IL-2, for example, is not adversely affected because other cytokines (IL-15, IL-7, IL-9, etc.) assume its function.  Similarly, a mutation in a cytokine receptor subunit other than the one in common often has little effect.  On the other hand, a mutation in the common subunit has profound effects.  For example, a mutation in the gene for the IL-2R gamma subunit causes human X-linked severe combined immunodeficiency (XSCID) characterized by a complete or nearly complete T and B cell defects.
One cytokine often influences the synthesis of other cytokines. They can produce cascades, or enhance or suppress production of other cytokines.  In addition, they can often influence the action of other cytokines. The effects can be:

• Antagonistic
• Additive
• Synergistic

Cytokines bind to specific receptors on target cells with high affinity and the cells that respond to a cytokine are either: 1) the same cell that secreted cytokine (autocrine); 2) a nearby cell (paracrine) or 3) a distant cell reached through the circulation (endocrine). Cellular responses to cytokines are generally slow (hours) because they require new mRNA and protein synthesis.
 

II. Categories of Cytokines

Cytokines can be grouped into different categories based on their functions or their source but it is important to remember that because they can be produced by many different cells and act on many different cells, any attempt to categorize them will be subject to limitations.

A. Mediators of natural immunity

Cytokines that play a major role in the innate immune system include: TNF-α, IL-1, IL-10, IL-12, type I interferons (IFN-α and IFN-β), IFN-γ, and chemokines.

1. TNF-α
Tumor necrosis factor alpha is produced by activated macrophages is response to microbes, especially the lipopolysaccharide (LPS) of Gram negative bacteria. It is an important mediator of acute inflammation. It mediates the recruitment of neutrophils and macrophages to sites of infection by stimulating endothelial cells to produce adhesion molecules and by producing chemokines which are chemotactic cytokines. TNF- α also acts on the hypothalamus to produce fever and it promotes the production of acute phase proteins.

2. IL-1
Interleukin 1 is another inflammatory cytokine produced by activated macrophages. Its effects are similar to that of TNF-α and it also helps to activate T cells.

3. IL-10
Interleukin 10 is produced by activated macrophages and Th2 cells. It is predominantly an inhibitory cytokine. It inhibits production of IFN-γ by Th1 cells, which shifts immune responses toward a Th2 type. It also inhibits cytokine production by activated macrophages and the expression of class II MHC and co-stimulatory molecules on macrophages, resulting in a dampening of immune responses.

4. IL-12
Interleukin 12 is produced by activated macrophages and dendritic cells. It stimulates the production of IFN-γ and induces the differentiation of Th cells to become Th1 cells. In addition, it enhances the cytolytic functions of Tc and NK cells.

5. Type I interferons
Type I interferons (IFN-α and IFN-β) are produced by many cell types and they function to inhibit viral replication in cells. They also increase expression of class I MHC molecules on cells making them more susceptible to killing by CTLs. Type I interferons also activate NK cells.

6. INF-γ
Interferon gamma is an important cytokine produced by primarily by Th1 cells, although it can also be produced by Tc and NK cells to a lesser extent. It has numerous functions in both the innate and adaptive immune systems as depicted in Figure 2.

7. Chemokines
Chemokines are chemotactic cytokines produced by many kinds of leukocytes and other cell types. They represent a large family of molecules that function to recruit leukocytes to sites of infection and play a role in lymphocyte trafficking.
 

B. Mediators of adaptive immunity

Cytokines that play a major role in the adaptive immune system include: IL-2, IL-4, IL-5, TGF-β, IL-10 and IFN-γ.

1. IL-2
Interleukin 2 is produced by Th cells, although it can also be produced by Tc cells to a lesser extent. It is the major growth factor for T cells. It also promotes the growth of B cells and can activate NK cells and monocytes as depicted in Figure 3. IL-2 acts on T cells in an autocrine fashion. Activation of T cells results in expression of IL-2R and the production of IL-2. The IL-2 binds to the IL-R and promotes cell division. When the T cells are no longer being stimulated by antigen, the IL-2R will eventually decay and the proliferative phase ends Figure 4.

2. IL-4
Interleukin 4 is produced by macrophages and Th2 cells. It stimulates the development of Th2 cells from naïve Th cells and it promotes the growth of differentiated Th2 cells resulting in the production of an antibody response. It also stimulates Ig class switching to the IgE isotype.

3. IL-5
Interleukin 5 is produced by Th2 cells and it functions to promote the growth and differentiation of B cells and eosinophiles. It also activates mature eosinophiles.

4. TGF-β
Transforming growth factor beta is produced by T cells and many other cell types. It is primarily an inhibitory cytokine. It inhibits the proliferation of T cells and the activation of macrophages. It also acts on PMNs and endothelial cells to block the effects of pro-inflammatory cytokines.

C. Stimulators of hematopoesis

Some cytokines stimulate the differentiation of hematopoetic cells. These include GM-CSF which promotes the differentiation of bone marrow progenitors, M-CSF, which promotes growth and differentiation of progenitors into monocytes and macrophages and G-CSF, which promotes production of PMNs.
 

III. Cytokine Networks

Although the focus has been on the production and action of cytokines on cells of the immune system, it is important to remember that many of them have effects on other cells and organ systems. A schematic diagram showing some of the interactions in the cytokine network is presented in Figure 5a, b and c.

IV. Immunoregulation

The magnitude of an immune response is determined by the balance between antigen-driven activation of lymphocytes and negative regulatory influences that prevent or dampen the response. Regulatory mechanisms can act at the recognition, activation or effector phases of an immune response. Examples of regulation that have already been discussed include:

• Recognition of antigen in the absence of co-stimulation resulting in anergy
• Recognition of antigen with CTLA-4 engagement of B7 resulting in down regulation of T cell activation
• Cytokines with stimulatory or inhibitory activities on immune cells
• Idiotype/anti-idiotype interactions leading to stimulation or inhibition of immune responses.

In addition to these there are other ways in which immune responses can be regulated.

A. Regulation by antibody (Figure 6)

Soluble antibody can compete with antigen receptors on B cells and block or prevent B cell activation. In addition antigen antibody complexes can bind to Fc receptors on B cells, sending an inhibitory signal to B cells.


B. Regulation by regulatory T cells (Tregs)

Regulatory T cells (Tregs) are a recently described populations of cells that can regulate immune responses. They do not prevent initial T cell activation; rather, they inhibit a sustained response and prevent chronic and potentially damaging responses. They do not have characteristics of Th1 or Th2 cells but they can suppress both Th1 and Th2 responses.

1. Naturally occurring Tregs – The thymus gives rise to CD4+/CD25+/Foxp3+ cells that functions as Tregs. These Tregs suppress immune responses in a cell contact dependent manner but the mechanism of suppression has not been established.

2. Induced Tregs – In the periphery some T cells are induced to become Tregs by antigen and either IL-10 or TGF-β. Tregs induced by IL-10 are CD4+/CD25+/Foxp3- and are referred to as Tr1 cells. These cells suppress immune responses by secretion of IL10. Tregs induced by TGF-β are CD4+/CD25+/Foxp3+ and are referred to as induced Tregs. These cells suppress by secretion of TGF-β

3. CD8+ Tregs – Some CD8+ cells can also be induced by antigen and IL-10 to become a Treg cell. These cells are CD8+/Foxp3+ and they suppress by a cell contact dependent mechanism or by secretion of cytokines. These cells have been demonstrated in vitro but it is not known whether they exist in vivo.
 

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