Interleukin-2

Author: Prof. Dr. med. Peter Altmeyer

Last updated on: 19.09.2022

Synonym(s)

blastogenic factor (BF); eosinophil differentiation factor (EDF); Factor from lymphocyte conditioned media (LCM factor); IL-2; Killer cell helper factor (KHF); Lymphocyte mitogenic factor (LMF); Lymphocyte proliferation factor (LPF); Lymphocyte proliferation factor (LPF),T cell growth factor; Macrophage activating factor for cytotoxicity I (MAF-C I); Plaque forming cell enhancing activity (PFC-EA); Secondary cytotoxic T cell-inducing factor (SCIF); T cell growth factor (TCGF); T cell maturation factor (TMF); T cell replacing factor 3 (TRF-3); T colony promoting activity (TCPA); Thymocyte differentiation factor (TDF); Thymocyte mitogenic factor (TMF); Thymocyte mitogenic protein (TMP); Thymocyte stimulating factor (TSF).

Definition
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Interleukin-2 is an endogenous glycoprotein (cytokine), which is encoded by the interleukin-2 gene on the 4th chromosome. The synthesis of interleukin-2 occurs on the one hand after antigen stimulation, on the other hand specifically by interleukins-1 and interleukin-6, as well as non-specifically by lectins and vitamin E (alphaTocopherol).

Cells capable of interleukin-2 production are:

NK cells
transformed B lymphocytes
leukemia cells and
LAK cells.

Interleukin-2 is the major activating cytokine for T cells expressing CD4 antigen (T helper cells). In a broader sense, the cytokine thus acts as a growth and differentiation factor for T cells.

General information
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Interleukin-2 acts through different membrane-bound interleukin-2 receptors(CD121a) expressed by T lymphocytes. The density of these receptors is 500-5000/cell in the resting state of the cells, and 12,000/cell in the activated state.

3 different receptor types are expressed: high affinity, medium affinity and low affinity receptors. They are also called alpha/beta/gamma chains:

the alpha chain(CD25), also called "T cell activation antigen", with low affinity
the beta chain (CD122), also "interleukin-2Rbeta".
the gamma chain (CD132), also "interleukin-2Rgamma".

These subunits are also parts of receptors of other cytokines.

The 3 receptor types are expressed separately but function together in different compositions as receptors with different affinities. The complex of alpha and gamma chains binds interleukin-2 with intermediate affinity; the high-affinity receptor is formed by a complex of all 3 chains (mainly by activated T cells and regulatory T cells).

In addition to membrane-bound IL-2 receptors, a soluble IL-2 receptor (sIL-2) circulating in plasma can also be detected. This is a fragment of a subunit. sIL-2R is increased in autoimmune diseases, infections, malignant myeloproliferative processes and other diseases of the immune system as well as after transplantation.

These different activities initiate 3 different intracellular signaling pathways: the MAP kinase pathway, the phosphoinositide-3-kinase (PI3K) pathway and the JAK-STAT pathway. Via this intracellular signaling cascade, peripheral blood T cells are differentiated into so-called lymphokine-activated killer (LAK) cells.

Activation of T lymphocytes leads to increased production of downstream cytokines (TNF, interferons). In addition to this "autocrine" co-directed T cell activation, interleukin-2 in B lymphocytes promotes the synthesis and secretion of immunoglobulins. Cyclosporin A and dexamethasone inhibit its synthesis in a dose-dependent manner.

General therapy
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Therapeutically, interleukin-2 was used with moderate success in the treatment of malignant (metastasized) tumors. Its functions can be inhibited therapeutically by blocking its receptor. The receptor antagonists basiliciximab and daclizumab are used for the prophylaxis of acute transplant rejection.

Literature
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Gillies SD et al (2011) A low-toxicity IL-2-based immunocytokine retains antitumor activity despite its high degree of IL-2 receptor selectivity. Clin Cancer Res 17:3673-3685.
Leong JW et al.(2014) Preactivation with IL-12, IL-15, and IL-18 induces CD25 and a functional high-affinity IL-2 receptor on human cytokine-induced memory-like natural killer cells. Biol Blood Marrow Transplant 20:463-473.
Liu Y et al (2012) Interleukin (IL)-6, tumour necrosis factor alpha (TNF-α) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: a meta-analysis and meta-regression. J Affect Disord 139:230-239.
Méndez-Lagares G et al (2014) HIV infection deregulates the balance between regulatory T cells and IL-2-producing CD4 T cells by decreasing the expression of the IL-2 receptor in Treg. J Acquir Immune Defic Syndr 65:278-282.
Minocha M et al (2016) Blockade of the High-Affinity Interleukin-2 Receptors with Daclizumab High-Yield Process: Pharmacokinetic/Pharmacodynamic Analysis of Single- and Multiple-Dose Phase I Trials. Clin Pharmacokinetics 55:121-130.
Smith GA et al(2016) Essential biphasic role for JAK3 catalytic activity in IL-2 receptor signaling. Nat Chem Biol 12:373-379.