Crystallographic structure of IL-2 (center alpha helices) complexed with the common gamma chain (IL2RG; 10 O'Clock to 1 O'Clock), IL2RA (4 O'Clock), and IL2RB (7 O'Clock to 9 O'Clock). Each protein is individually rainbow colored (N-terminus = blue, C-terminus = red).1
This protein is located on the surface of immature blood-forming cells in bone marrow. One end of the protein resides outside of the cell where it binds to cytokines and the other end of the protein resides in the interior of the cell where it transmits signals to the cell's nucleus. The common gamma chain partners with other proteins to direct blood-forming cells to form lymphocytes (a type of white blood cell). The receptor also directs the growth and maturation of lymphocyte subtypes: T cells, B cells, and natural killer cells. These cells kill viruses, make antibodies, and help regulate the entire immune system.
Cytokine receptor common subunit gamma also known as interleukin-2 receptor subunit gamma or IL-2RG is a protein that in humans is encoded by the IL2RGgene.5 The human IL2RG gene is located on the long (q) arm of the X chromosome at position 13.1, from base pair 70,110,279 to base pair 70,114,423.
IL-7 receptor and signaling, common γ chain (blue) and IL-7 receptor-α (green)
Lymphocytes expressing the common gamma chain can form functional receptors for these cytokine proteins, which transmit signals from one cell to another and direct programs of cellular differentiation.
X-linked severe combined immunodeficiency is caused by mutations in the IL2RG gene. More than 200 different mutations in the IL2RG gene have been identified in people with X-linked severe combined immunodeficiency (SCID).9 Most of these mutations involve changes in one or a few DNA building blocks (nucleotides) in the gene. These changes lead to the production of a nonfunctional version of the common gamma chain proteincitation needed or no production of protein.10 Without the common gamma chain, important chemical signals are not relayed to the nucleus and lymphocytes cannot develop normally. A lack of functional mature lymphocytes disrupts the immune system's ability to protect the body from infection. Sufferers have no functional immunity and can die within months after birth without successful bone marrow transplantation or alternatively, isolation from exposure to pathogens. Without important developmental signals from IL-7 and IL-15, T-cell and NK cell populations respectively fail to develop.
Experiments in animal models have shown X-SCID to occur similarly in dogs, but not in mice.11
^Russell SM, Keegan AD, Harada N, Nakamura Y, Noguchi M, Leland P, Friedmann MC, Miyajima A, Puri RK, Paul WE (December 1993). "Interleukin-2 receptor gamma chain: a functional component of the interleukin-4 receptor". Science262 (5141): 1880–3. doi:10.1126/science.8266078. PMID8266078.
^Noguchi M, Nakamura Y, Russell SM, Ziegler SF, Tsang M, Cao X, Leonard WJ (December 1993). "Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor". Science262 (5141): 1877–80. doi:10.1126/science.8266077. PMID8266077.
^Takeshita T, Asao H, Ohtani K, Ishii N, Kumaki S, Tanaka N, Munakata H, Nakamura M, Sugamura K (July 1992). "Cloning of the gamma chain of the human IL-2 receptor". Science257 (5068): 379–82. doi:10.1126/science.1631559. PMID1631559.
^Asao H, Okuyama C, Kumaki S, Ishii N, Tsuchiya S, Foster D, Sugamura K (July 2001). "Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex". J. Immunol.167 (1): 1–5. PMID11418623.
^Miyazaki T, Kawahara A, Fujii H, Nakagawa Y, Minami Y, Liu ZJ, Oishi I, Silvennoinen O, Witthuhn BA, Ihle JN (November 1994). "Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits". Science266 (5187): 1045–7. doi:10.1126/science.7973659. PMID7973659.
^Russell SM, Johnston JA, Noguchi M, Kawamura M, Bacon CM, Friedmann M, Berg M, McVicar DW, Witthuhn BA, Silvennoinen O (November 1994). "Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID". Science266 (5187): 1042–5. doi:10.1126/science.7973658. PMID7973658.
^Vihinen M, Arredondo-Vega FX, Casanova JL, Etzioni A, Giliani S, Hammarström L, Hershfield MS, Heyworth PG, Hsu AP, Lähdesmäki A, Lappalainen I, Notarangelo LD, Puck JM, Reith W, Roos D, Schumacher RF, Schwarz K, Vezzoni P, Villa A, Väliaho J, Smith CI (2001). "Primary immunodeficiency mutation databases". Adv. Genet.43: 103–88. PMID11037300.
Takeshita T, Asao H, Ohtani K, Ishii N, Kumaki S, Tanaka N, Munakata H, Nakamura M, Sugamura K (July 1992). "Cloning of the gamma chain of the human IL-2 receptor". Science257 (5068): 379–82. doi:10.1126/science.1631559. PMID1631559.
Ohbo K, Takasawa N, Ishii N, Tanaka N, Nakamura M, Sugamura K (March 1995). "Functional analysis of the human interleukin 2 receptor gamma chain gene promoter". J. Biol. Chem.270 (13): 7479–86. doi:10.1074/jbc.270.13.7479. PMID7706294.
Russell SM, Johnston JA, Noguchi M, Kawamura M, Bacon CM, Friedmann M, Berg M, McVicar DW, Witthuhn BA, Silvennoinen O (November 1994). "Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID". Science266 (5187): 1042–5. doi:10.1126/science.7973658. PMID7973658.
Ishii N, Asao H, Kimura Y, Takeshita T, Nakamura M, Tsuchiya S, Konno T, Maeda M, Uchiyama T, Sugamura K (August 1994). "Impairment of ligand binding and growth signaling of mutant IL-2 receptor gamma-chains in patients with X-linked severe combined immunodeficiency". J. Immunol.153 (3): 1310–7. PMID8027558.
Johnson K, Choi Y, Wu Z, Ciardelli T, Granzow R, Whalen C, Sana T, Pardee G, Smith K, Creasey A (1994). "Soluble IL-2 receptor beta and gamma subunits: ligand binding and cooperativity". Eur. Cytokine Netw.5 (1): 23–34. PMID8049354.
Markiewicz S, Subtil A, Dautry-Varsat A, Fischer A, de Saint Basile G (May 1994). "Detection of three nonsense mutations and one missense mutation in the interleukin-2 receptor gamma chain gene in SCIDX1 that differently affect the mRNA processing". Genomics21 (1): 291–3. doi:10.1006/geno.1994.1265. PMID8088810.
Kondo M, Takeshita T, Ishii N, Nakamura M, Watanabe S, Arai K, Sugamura K (December 1993). "Sharing of the interleukin-2 (IL-2) receptor gamma chain between receptors for IL-2 and IL-4". Science262 (5141): 1874–7. doi:10.1126/science.8266076. PMID8266076.