Overview of Common Gamma Chain Receptor Family
Interleukin IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 share a common cytokine receptor γ chain (γc), so they together form the common gamma chain receptor family. γc was firstly discovered as the third receptor component of the IL-2 receptor, IL-2Rγ. The γc subunit links and other different cytokine-specific receptor subunits form unique heterodimeric receptors for IL-4, IL-7, IL-9, and IL-21, or together with both IL-2/IL-15 Rβ and IL-2 Rα or IL-15 Rα, form heterotrimeric receptors for IL-2 or IL-15, respectively. Three major signaling pathways, the PI 3-K-Akt pathway, the Ras-MAPK pathway, and the JAK-STAT pathway, are activated by γc family cytokines, which promote cellular survival and proliferation.
Common Gamma Chain Receptor Family
CD4+ T cells are the main producer of IL-2 in response to T-cell receptor (TCR) stimulation. Otherwise, CD8+ T cells, NK cells, and NK T (NKT) cells can also produce IL-2 but at much lower levels. In addition, IL-2 can also induce activation-induced cell death (AICD) of CD4+ T cells, which is crucial for the maintenance of peripheral self-tolerance. Another essential role of IL-2 in vivo is to promote the development and maintenance of regulatory T (Treg) cells whose suppressive activity is important to control pathologic inflammatory responses. Consequently, IL-2 has been extensively used as an anticancer agent and a modulator of immune system.
Firstly, IL-4 was identified as a B-cell differentiation factor produced by T cells. IL-4 can be regarded as a signature cytokine for Th2 responses which are vital for the control of extracellular parasites infection and contribute to allergic reactions. In addition, the generation of M2 (M-IL-4) macrophages is induced by IL-4, which is important for macrophage-mediated control of infection with the protozoan Trypanosoma cruzi. Because of its key role in mediating allergic responses, the modulation of IL-4 activity is of considerable therapeutic interest.
Unlike the production of IL-2 and IL-4 from T cells, IL-7 was discovered as a stromal-cell-derived factor which supported the growth of pre-B cells. Also, IL-7 signaling plays an essential, nonredundant role in the development of T cells in humans, and both B and T cells in mice. The expression level of IL-7 is relatively stable compared with other γc family cytokines. IL-7 itself does not promote the proliferation of naive T cells. However, it is important to ensure sustained expression of antipoptotic proteins BCL2 and MCL1 for the long-term in vivo survival of T cells.
IL-9 was firstly discovered as a Th2 cytokine, and now, it is recognized as the signature cytokine for Th9 cells. IL-9 can support innate lymphoid-cell (ILC) survival and enhance IL-4 induced IgE and IgG production. IL-9 can also be produced by Th17 cells and promote the expansion of these cells. In NKT cells, expression of IL-9 can be enhanced by IL-2 but not IL-15.
IL-15 was identified as a T-cell growth factor at first. Although IL-15 messenger RNA (mRNA) can be expressed by many different cell types, IL-15 protein is mainly produced by dendritic cells (DCs) and monocytes when it is activated by Toll-like receptor (TLR) and binds to receptors on these cells. IL-15 plays an important role in the development of memory CD8+ T cells and can especiallyexpand central memory phenotype T cells in vivo.
IL-21 was firstly recognized as a ligand for the type 1 cytokine receptor. IL-21 plays complex roles in the differentiation and function of B cells. For example, without anti-CD40 or anti-IgM, IL-21 can promote the B-cell differentiation. However, IL-21 also induces the death of resting B cells or B cells stimulated with lipopoplysaccharide (LPS) or CpG. In addition, IL-21 can also increase the numbers of CD56+ CDhigh human NK cells which are generated from CD34+ human hematopoietic progenitor cells cultured with IL-15 and Flt3 ligand. The growth of naive or memory CD8+ T cells cannot be increased largely by IL-21 itself. However, IL-21 can promote the proliferation of these cells by synergizing with IL-15 and IL-7.
Relations with Human Diseases
As discussed above, γc family cytokines play an important role in the development of T and NK cells, the function of B cells and other immune cells. It is crucial to keep a balanced action of these cytokines to protect the host from harm not only caused by pathogens but also by inflammation which is resulted from immune responses.
A number of evidence have indicated that the effector CD4+ T cells play key roles in mediating autoimmune pathology, and Tregs play a crucial role in controlling the immune response. Human autoimmune disorders are related with the abnormal of γc family cytokines. Therefore, modulating γc family cytokines signals is a crucial measure to manage autoimmunity. For example, Systemic lupus erythematosus (SLE) is a systemic autoimmune disease whose cause we still don’t know. It is characterized by massive production of autoantibodies and proinflammatory cytokines and can affect every organ. There is a study of 1318 SLE patients and 1318 matched controls which found that two of three SNPs in the introns of IL-21 were significantly related to SLE.