Interleukin2

IL-2, also known as T-cell growth factor, represents the most studied member of the interleukin family. It was the first T-cell growth factor to be identified and it plays a central role in the immune response. It is produced exclusively by T-lymphocytes (especially T-helper cells), in response to activation by antigen and mitogens.

Human IL-2 is a single-chain polypeptide containing 133 amino acids. It is a glycoprotein, the carbohydrate component being attached via an O-linked glycosidic bond to threonine

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Figure 9.1 Three-dimensional structure of IL-2. Structural details courtesy of the Protein Data Bank, http:// www.rcsb.org/pdb/

residue no. 3. The mature molecule displays a molecular mass ranging from 15 to 20 kDa, depending upon the extent of glycosylation. The carbohydrate moiety is not required for biological activity.

X-ray diffraction analysis shows the protein to be a globular structure, consisting of four a-heli-cal stretches interrupted by bends and loops. It appears devoid of any P-conformation and contains a single stabilizing disulfide linkage involving cysteine numbers 58 and 105 (Figure 9.1).

IL-2 induces its characteristic biological activities by binding a specific receptor on the surface of sensitive cells. The high-affinity receptor complex consists of three membrane-spanning polypeptide chains (a, P and y, Table 9.2).

Table 9.2 Summary of the polypeptide constituents of the high-affinity human IL-2 receptor

Receptor polypeptide constituent

Additional names

Molecular mass (kDa)

a

P55

Tac

55

CD25

P75

CD122

75

Y

P64

64

Figure 9.2 Schematic diagram of the high affinity IL-2 receptor

The a chain binds IL-2 with low affinity, with binding being characterized by high subsequent association-disassociation rates. The y subunit does not interact directly with IL-2. It is sometimes known as yc (common), as it also appears to be a constituent of the IL-4, -7, -9, -13 and -15 recep-

Heterodimeric complexes consisting of ay or Py can bind IL-2 with intermediate affinity. The heterotrimeric aPy complex represents the cytokine's true high-affinity receptor (Figure 9.2). The exact intracellular signal transduction events triggered by IL-2 are not fully elucidated. The a receptor chain exhibits a cytoplasmic domain containing only nine amino acids, and is unlikely to play a role in intracellular signalling. Mutational studies reveal that the 286 amino acid P chain intracellular domain contains at least two regions (a serine-rich region and an acidic region) essential for signal transduction. The P chain is phosphorylated on a specific tyrosine residue subsequent to IL-2 binding, probably via association of a protein tyrosine kinase essential for generation of intracellular signals. The direct role played by the y chain, although unclear, is likely critical. A mutation in the gene coding for this receptor constituent results in severe combined immunodeficiency (X-SCID).

Interestingly, prolonged elevated levels of IL-2 promote the shedding of the IL-2 receptor a subunit from the cell surface. Initially, it was suspected that these circulating soluble receptor fragments, capable of binding IL-2, might play a role in inducing immunosuppression (by competing for IL-2 with the cell surface receptor). However, the affinity of IL-2 for the intact receptor (aPy) is far greater than for the a subunit, rendering this theory unlikely.

The IL-2 receptor is associated with a number of cell types, mainly cells playing a central role in the immune response (Table 9.3). Binding of IL-2 to its receptor induces growth and

Table 9.3 The range of cells expressing the IL-2 cell surface receptor. IL-2-stimulated growth and differentiation of these cells forms the molecular basis by which many aspects of the immune response are activated. It thus acts in an autocrine and paracrine manner to mobilize the immune response

T-lymphocytes B-lymphocytes

NK cells LAK cells

Monocytes Macrophages

Oligodendrocytes

I___Presented antigen jl-2

T-cell receptor recognizing antigen

T-cell receptor recognizing antigen

Synthesis and release of additional cytokines, including IL-3, 4, 5 & 6, IFN g and TNF b

Figure 9.3 Activation of T-ceLLs by interaction with macrophage-displayed antigen. Activation results in IL-2 production, which acts in an autocrine manner to stimulate further T-cell growth and division. IL-2 thus represents the major regulatory molecule responsible for stimulation of cell-mediated immunity. Note that it was initially believed that binding of presented antigen alone was insufficient to trigger T-cell activation. It was thought that co-stimulation with IL-1 was required. However, the assay used to detect the 'co-stimulation' was found not to be specific for IL-1 alone. The role of IL-1 as a co-stimulator of T-cell activation is now believed to be minimal at most differentiation of these cells. This cytokine, therefore, behaves as a central molecular switch, activating most aspects of the immune response.

Quiescent T-lymphocytes are stimulated largely by direct binding to an antigen fragment presented on the surface of a macrophage in the context of MHC complex (Figure 9.3). This results in the induction of expression of at least 70 genes whose products are collectively important in immune stimulation. These products include:

• Several cytoplasmic proteins capable of inducing T-cell growth (i.e. several cellular proto-oncogenes, including C-fos and C-myc).

• Various cytokines, most notably IL-2.

• Cytokine receptors, most notably the IL-2 receptor a subunit. (The T-lymphocytes appear to constitutively express the P and y IL-2 receptor polypeptides. Induction of the a gene leads to formation of a high-affinity aPY receptor complex, thereby rendering the activated T cell highly sensitive to IL-2.)

IL-2 acts as a critical autocrine growth factor for T-cells, and the magnitude of the T-cell response is largely dependent upon the level of IL-2 produced. IL-2 also serves as a growth factor for activated B-lymphocytes. In addition to promoting proliferation of these cells, IL-2 (as well as some other interleukins) stimulates enhanced antibody production and secretion. In this way, it effectively potentates the humoral immune response.

A third biological activity of IL-2 pertinent to immunostimulation is its ability to promote the growth of NK cells. It also promotes further differentiation of NK cells, forming lymphokine-activated killer (LAK) cells, which exhibit an enhanced ability to kill tumour cells or virally infected cells directly. NK cells express the P and y IL-2 receptor subunits only; thus, their stimulation by IL-2 requires elevated concentrations of this cytokine. NK cells are also activated by a variety of additional cytokines, including all interferons and TNF.

The immunopotentative effects of IL-2 rendered it an obvious target for clinical application. At the simplest level, it was hoped that administration of exogenous IL-2 could enhance the immune response to a number of clinical conditions, including:

• T-cell and other forms of immunodeficiency,

• infectious diseases.

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