Interleukin-2 (IL-2): characteristics and reception
IL-2 is the first discovered lymphokine, which is a monomeric glycoprotein (15–22 kDa). Its main producers are activated CD4+ T lymphocytes (at the Th0 stage). Following differentiation, synthesis is maintained only in Th1 cells, but gradually fades.
The IL-2 receptor consists of three transmembrane chains:
- $\beta$- and $\gamma$-chains: expressed constitutively on T and NK cells. By themselves, they have low affinity for the cytokine and are unable to transduce a signal.
- $\alpha$-chain: induced only after cell activation.
A functional high-affinity receptor is formed upon assembly of all three chains ($\alpha\beta\gamma$). Such a trimer binds IL-2, generates a signal, and ensures internalization—uptake of the complex into the cell for the destruction of the spent cytokine. In NK cells, the $\alpha$-chain is typically absent, and the $\beta\gamma$ receptor operates.
Intracellular IL-2 signal transduction
Binding of IL-2 to its receptor induces conformational changes that activate several cascades:
- Jak/STAT pathway: Jak1 kinase (associated with the $\beta$-chain) and Jak3 (associated with the $\gamma$-chain) phosphorylate STAT3 and STAT5 factors. The resulting dimers translocate to the nucleus and regulate the cell cycle.
- Interaction with Lck: Jak kinases phosphorylate the carboxyl residues of the receptor, recruiting the Lck kinase.
- Ras/Raf pathway (MAP cascade): triggered via Lck to generate factors that propel the cell through the mitotic cycle.
- PI3K/Vav pathway: Lck activates PI3K, which turns on the Vav protein—a key factor in cytoskeleton remodeling for mitosis.
The end result is robust antigen-independent proliferation of T cells. Meanwhile, IL-2 is critically important for inducing the differentiation and growth of regulatory T lymphocytes ($T_{reg}$). Deficiency of the IL2 gene leads to autoimmune diseases due to the loss of $T_{reg}$ control.
Interleukin-4 (IL-4): humoral immunity
IL-4 is a glycoprotein synthesized predominantly by Th2 cells, as well as mast cells and basophils. It is the only cytokine that induces the differentiation of naive T cells into the Th2 subset. The IL-4 receptor includes an $\alpha$-chain and a shared $\gamma(c)$-chain.
Effects of IL-4 on cells:
- B lymphocytes: serves as the primary growth factor. Induces class switching of genes to synthesize IgE (in humans) and IgG1 (in mice) immunoglobulin isotypes. Increases the expression of the Fc$\varepsilon$RII (CD23) receptor.
- Macrophages: exerts a pronounced anti-inflammatory effect by suppressing the synthesis of pro-inflammatory cytokines (IL-1, TNF$\alpha$, IL-6), but paradoxically enhances their cytotoxicity.
- T lymphocytes: acts as a "backup" growth factor substituting for IL-2.
IL-4 is a major driver of allergies because it stimulates IgE synthesis and supports the growth of connective tissue mast cells. It often acts as an antagonist to IFN$\gamma$, suppressing its effects, yet they exhibit synergy in upregulating MHC-II molecule expression.
Interleukins 5 and 13 (IL-5, IL-13)
Interleukin-5 (a homodimer) is secreted by Th2 cells and mast cells. It has a narrow but vital range of targets:
- Eosinophils: IL-5 is the main factor for their survival, growth, and chemotaxis. It plays a central role in the development of the late-phase immediate-type allergic reaction.
- B lymphocytes: supports late stages of proliferation, stimulates plasmacyte formation, and increases IgA production for mucosal defense.
Interleukin-13 is a 10 kDa cytokine. Its gene is located in the same cluster as the IL4 gene, and IL-13 can duplicate many functions of IL-4 due to the shared $\alpha$-chain in their receptors. In addition to B cells and eosinophils, IL-13 actively acts on smooth muscle and goblet cells, stimulating abundant mucus production in the epithelium.
Remember the "allergic triad" of Th2 cells: IL-4 turns on IgE (humoral response), IL-5 calls in eosinophils (cellular phase), and IL-13 forces goblet cells to secrete mucus.
Class and exam questions
What is IL-2 superinduction?
This is a sharp amplification of cytokine production that occurs under the influence of ionizing radiation (10–15 Gy) or protein synthesis inhibitors (due to the presence of stable mRNA and the removal of inhibitory control).
How does IL-2 affect hematopoiesis?
It enhances platelet and eosinophil production, promotes the appearance of extramedullary hematopoiesis foci, while weakening myelopoiesis and erythropoiesis.
What are the consequences of an IL-2 gene knockout?
To the development of autoimmune polyendocrinopathies and benign lymphoproliferative processes (especially in the intestine), as IL-2 is indispensable for maintaining the population of regulatory T lymphocytes.
What are the similarities between IL-4 and IL-13 receptors?
Their effects largely overlap because the receptors for both cytokines utilize a shared $\alpha$-chain (IL-R4$\alpha$). The difference is that the IL-13 receptor contains its own IL-13R$\alpha$ instead of the $\gamma(c)$-chain.
What else to study on this topic
- Mechanisms of LAK cell (lymphokine-activated killer cell) generation induced by IL-2.
- Features of intercellular interaction between Th1 and Th2 cytokines (synergy and antagonism).
- The genetic cluster of Th2 cytokines on chromosome 5: regulation of expression.
- Structure and functions of the Fc$\varepsilon$RII (CD23) receptor and its soluble form in the pathogenesis of allergy.
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