Common Gamma-Chain Cytokine Family Review

The gamma-chain (γc) cytokine receptor is the shared receptor subunit for the six cytokines IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, which are collectively referred to as common gamma-chain cytokine family.

Members of the common gamma-chain cytokine family play distinct and nonredundant roles in the adaptive immune system, and especially in the development and differentiation of T lymphocytes.

The importance of the common gamma-chain in the immune system is illustrated by the profound phenotype associated with gamma-chain gene deficiency that manifests as T-, NK cell deficiency in humans and as T-, B-, NK cell deficiency in mice. Thus, common gamma-chain expression is a non-redundant requirement for lymphocytes, and especially critical for T cells in both humans and mice.

Below will briefly discuss each common gamma-chain (γc) cytokine family member and their functions, including interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-7 (IL-7), interleukin-9 (IL-9), interleukin-15 (IL-15) and interleukin-21 (IL-21).

Interleukin-2 (IL-2)

IL-2 is a member of common gamma-chain (γc) cytokine family. Discovered more than 30 years ago in supernatants of activated T cells, IL-2 is mainly produced by CD4 and CD8 T cells, and to a lesser extent by activated DCs and NK and NK T (NKT) cells. The IL-2 receptor consists of 3 subunits: the ligand-specific αlpha chain IL-2Rα (CD25), the beta chain IL-2Rβ (CD122, which is also part of the IL-15 receptor complex), and the common gamma chain (CD132). All three subunits are required for the assembly of the high-affinity IL-2 receptor.

On T-cell activation, IL-2Rα is rapidly induced and participates in formation of a high-affinity quaternary complex, which activates multiple signal transduction pathways. IL-2 is essential for the development of Treg cells. IL-2 also acts as a B-cell growth factor, stimulates antibody synthesis, and promotes proliferation and differentiation of NK cells to increase their cytolytic functions. Recombinant human IL-2 is used in immunotherapy for cancer and AIDS associated with HIV. Anti–IL-2Rα inhibits the immune response in patients with autoimmune diseases and prevents rejection of transplanted organs.

Interleukin-4 (IL-4)

IL-4 belongs to common gamma-chain (γc) cytokine family and is a 15-kd monomer (129 amino acids) produced by TH2 cells, basophils, mast cells, and eosinophils. There are two types of IL-4 receptors. Type I IL-4 receptor binds only IL-4 and consists of two receptor chains: IL-4Rα (CD124) and the common gamma chain (CD132). Type II IL-4 receptor binds IL-4 and IL-13 and consists of the IL-4Rα and the IL-13Rα1 chains.

A pleiotropic cytokine, IL-4 regulates allergic conditions and the protective immune response against helminths and other extracellular parasites. IL-4 is the major stimulus of TH2-cell development; it also suppresses TH1-cell development and induces IgE classswitching in B cells. IL-4 increases the expression of class II MHC molecules in B cells, upregulates B-cell receptors, increases expression of CD23, prolongs lifespans of T and B cells in culture, and mediates tissue adhesion and inflammation. IL-4 and IL-4Rα knockout mice have defects in TH2-cell differentiation and reduced serum levels of IgG1 and IgE.

Interleukin-7 (IL-7)

IL-7, also known as pre–B-cell growth factor or lymphopoietin-1, is a homeostatic cytokine. The IL-7 receptor is present on most T cells, progenitors of B cells, and bone marrow macrophages; it consists of the IL-7Rα (CD127) chain and the common gamma chain (CD132). Because the common gamma chain is ubiquitously expressed on lymphocytes, IL-7 responses are determined by the expression of IL-7Rα, which is shared with thymic stromal lymphopoietin (TSLP) receptor.

IL-7 signaling contributes to survival and proliferation of thymocytes and development of naive and memory B and T cells, mature T cells, and NK cells. Studies of IL-7 and IL-7Rα knockout mice have shown that IL-7 is important for homeostatic T-cell and B-cell development. IL-7 or reagents that block IL-7 signaling might be used to treat patients with HIV-associated immunodeficiency and immunodeficiency secondary to chemotherapy, autoimmune diseases, and lymphoid malignancies.

Interleukin-9 (IL-9)

IL-9 was first discovered in mice, where it was found to be a potent, antigen-independent growth factor for T cells and mast cells. TH2 cells are the main source of IL-9 production; mast cells (mainly within the airways of subjects with asthma) and eosinophils secrete IL-9 to a lesser extent. IL-9 inhibits cytokine production by TH1 cells, promotes IgE production by B cells, induces chemokine and mucus secretion by bronchial epithelial cells, and promotes proliferation of mast cells.

The IL-9 receptor consists of the ligand-specific alpha-chain (IL-9Rα) and the common gamma chain (CD132). The IL-9Rα chain is sufficient to bind IL-9 with high affinity but does not mediate any signal by itself. IL-9 has important roles in pathogenesis of asthma and allergies and in fighting helminth infections. A new population of T cells, TH9 cells that produce IL-9 and IL-10, have been proposed to contribute to inflammation.

Interleukin-15 (IL-15)

IL-15 is structurally homologous to IL-2 and was discovered for its ability to induce T-cell proliferation like IL-2. Many of the biological actions attributed to IL-2 can also be induced by IL-15. The IL-15 receptor consists of the IL-15Rα chain, the IL-2Rβ chain, and the common gamma chain (CD132).

IL-15 is produced by nonimmune cells (keratinocytes and skeletal muscle cells) and immune cells (monocytes and activated CD4 T cells) in response to signals that induce innate immunity. Although IL-15 shares some functions with IL-2, such as activation of T cells, stimulation of NK-cell proliferation, and cytolytic activity, differences in their biological functions have been identified on the basis of differences observed between phenotypes of IL-2 and IL-15 knockout mice.

Interleukin-21 (IL-21)

IL-21 is produced by T cells, NKT cells, and the TH17 subset of CD4 T cells. The receptor for IL-21 is expressed on various cells, indicating a broad spectrum of action. IL-21 affects B-cell functions by regulating antibody isotype balance, proliferation, apoptosis, and differentiation into plasma cells. Cytotoxic activity and proliferation of CD8 T cells, NK cells, and NKT cells increase on stimulation with IL-21.

IL-21 has been tested as an anticancer drug, and first clinical trial results are promising by slowing down tumor progression in metastatic melanoma. In contrast with its anticancer effects, IL-21 also contributes to inflammation in several disorders, as expected for a TH17-related cytokine.

References

1. Akdis, M., Burgler, S., Crameri, R., Eiwegger, T., Fujita, H., Gomez, E., ... & Rhyner, C. (2011). Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases. Journal of allergy and clinical immunology, 127(3), 701-721.
2. Waickman, A. T., Park, J. Y., & Park, J. H. (2016). The common γ-chain cytokine receptor: tricks-and-treats for T cells. Cellular and molecular life sciences, 73(2), 253-269.