Immune response - IL-7 signaling in T lymphocytes

print

Select Species:

Click on a target from the pathway image to view related information. Zoom     View Legend

photo_map
 


IL-7 signaling in T lymphocytes

Interleukin-7 (IL-7) is an essential cytokine for proliferation, maintenance and survival of T-lymphocytes [1]. IL-7 receptor activates pathways that regulate lymphocyte survival, glucose uptake, proliferation and differentiation [2].

IL-7 receptor consists of the IL-7 receptor alpha chain (IL7RA) and the common cytokine gamma chain (IL-2R gamma chain) [1]. IL-7 ligation to the IL-7 receptor stimulates the trans-phosphorylation of receptor associated Janus kinases 1 and 3 (JAK1 and JAK3), which in turn phosphorylate tyrosine residues on the receptors themselves [3], [4], [5].

IL-7 receptor serves as docking sites for SH2 domain proteins including the Signal transducers and activators of transcription family of transcription factors (STAT1, STAT3, STAT5 and STAT6) which are activated by JAK-mediated phosphorylation [6], [7]. STAT5 promotes transcription of B-cell CLL/lymphoma 2 (Bcl-2) stimulating cell survival [8]. STAT5 promotes transcription of Suppressor of cytokine signaling 1 (SOCS1) inducing negative feed-back on IL-7 signaling [9], [10].

IL-7 receptor induces JAKs/ PTK2B protein tyrosine kinase 2 beta (Pyk2(FAK2)) cascade that participates in activation of T cell survival [5].

Activated IL-7 receptor stimulates Phosphatidylinositol 3-kinase (PI3K)/ V-akt murine thymoma viral oncogene (AKT/PKB) cascade via JAKs/ Insulin receptor substrates 1 and 2 (IRS-1, IRS-2) [11], [12] and/or Src family kinases FYN oncogene related to SRC (Fyn) and Lymphocyte-specific protein tyrosine kinase (Lck) [4], [13]. Activated PI3K induces conversion from Phosphatidyl-4,5-inositol bisphosphate (PtdIns(4,5)P2) to Phosphatidyl-3,4,5-inositol triphosphate (PtdIns(3,4,5)P3). PtdIns(3,4,5)P3 in turn induces AKT/PKB and 3-phosphoinositide dependent protein kinase-1 (PDK (PDPK1)) activation that promotes T lymphocytes proliferation and survival [14], [15].

AKT/PKB complex induces Solute carrier family 2 member 1 (GLUT1) activation inhibition of transcriptional factor Forkhead box O3 (FOXO3A). GLUT1 stimulates Glucose uptake thus promoting cell survival [16].

IL-7 stimulates V(D)J recombination of T-cell receptor gamma chain (TCR gamma locus) in T cells. V(D)J recombination is assemblage of mature genes encoding the component chains of TCR and immunoglobulin proteins from germ-line arrays of variable (V), diversity (D), and joining (J) gene segments during lymphoid development [17], [18]. STAT5 plays a key role in synthesis and V(D)J recombination of TCR gamma locus with participation of histone acetylases p300 and CBP [19]. It is possibly, that AKT/PKB-dependent inhibition Forkhead box O1 (FKHR) stimulates Recombination activating gene 1 and 2 (RAG1 and RAG2) transcription, thus inducing V(D)J recombination of TCR gamma locus. The RAG1/ RAG2 dimer recognizes the synapsis formed by the recognition motifs and initiates the cleavage step of V(D)J recombination [10], [17], [20].

References:

  1. Kittipatarin C, Khaled AR
    Interlinking interleukin-7. Cytokine 2007 Jul;39(1):75-83
  2. Palmer MJ, Mahajan VS, Trajman LC, Irvine DJ, Lauffenburger DA, Chen J
    Interleukin-7 receptor signaling network: an integrated systems perspective. Cellular & molecular immunology 2008 Apr;5(2):79-89
  3. Johnston JA, Bacon CM, Finbloom DS, Rees RC, Kaplan D, Shibuya K, Ortaldo JR, Gupta S, Chen YQ, Giri JD
    Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15. Proceedings of the National Academy of Sciences of the United States of America 1995 Sep 12;92(19):8705-9
  4. Sharfe N, Dadi HK, Roifman CM
    JAK3 protein tyrosine kinase mediates interleukin-7-induced activation of phosphatidylinositol-3' kinase. Blood 1995 Sep 15;86(6):2077-85
  5. Benbernou N, Muegge K, Durum SK
    Interleukin (IL)-7 induces rapid activation of Pyk2, which is bound to Janus kinase 1 and IL-7Ralpha. The Journal of biological chemistry 2000 Mar 10;275(10):7060-5
  6. Rosenthal LA, Winestock KD, Finbloom DS
    IL-2 and IL-7 induce heterodimerization of STAT5 isoforms in human peripheral blood T lymphoblasts. Cellular immunology 1997 Nov 1;181(2):172-81
  7. Qin JZ, Kamarashev J, Zhang CL, Dummer R, Burg G, Döbbeling U
    Constitutive and interleukin-7- and interleukin-15-stimulated DNA binding of STAT and novel factors in cutaneous T cell lymphoma cells. The Journal of investigative dermatology 2001 Sep;117(3):583-9
  8. Gatzka M, Piekorz R, Moriggl R, Rawlings J, Ihle JN
    A role for STAT5A/B in protection of peripheral T-lymphocytes from postactivation apoptosis: insights from gene expression profiling. Cytokine 2006 May;34(3-4):143-54
  9. Cornish AL, Chong MM, Davey GM, Darwiche R, Nicola NA, Hilton DJ, Kay TW, Starr R, Alexander WS
    Suppressor of cytokine signaling-1 regulates signaling in response to interleukin-2 and other gamma c-dependent cytokines in peripheral T cells. The Journal of biological chemistry 2003 Jun 20;278(25):22755-61
  10. Ramanathan S, Gagnon J, Leblanc C, Rottapel R, Ilangumaran S
    Suppressor of cytokine signaling 1 stringently regulates distinct functions of IL-7 and IL-15 in vivo during T lymphocyte development and homeostasis. Journal of immunology (Baltimore, Md. : 1950) 2006 Apr 1;176(7):4029-41
  11. Johnston JA, Wang LM, Hanson EP, Sun XJ, White MF, Oakes SA, Pierce JH, O'Shea JJ
    Interleukins 2, 4, 7, and 15 stimulate tyrosine phosphorylation of insulin receptor substrates 1 and 2 in T cells. Potential role of JAK kinases. The Journal of biological chemistry 1995 Dec 1;270(48):28527-30
  12. Sharfe N, Roifman CM
    Differential association of phosphatidylinositol 3-kinase with insulin receptor substrate (IRS)-1 and IRS-2 in human thymocytes in response to IL-7. Journal of immunology (Baltimore, Md. : 1950) 1997 Aug 1;159(3):1107-14
  13. Venkitaraman AR, Cowling RJ
    Interleukin 7 receptor functions by recruiting the tyrosine kinase p59fyn through a segment of its cytoplasmic tail. Proceedings of the National Academy of Sciences of the United States of America 1992 Dec 15;89(24):12083-7
  14. Cantley LC
    The phosphoinositide 3-kinase pathway. Science (New York, N.Y.) 2002 May 31;296(5573):1655-7
  15. Abell K, Watson CJ
    The Jak/Stat pathway: a novel way to regulate PI3K activity. Cell cycle (Georgetown, Tex.) 2005 Jul;4(7):897-900
  16. Wofford JA, Wieman HL, Jacobs SR, Zhao Y, Rathmell JC
    IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. Blood 2008 Feb 15;111(4):2101-11
  17. Huang J, Muegge K
    Control of chromatin accessibility for V(D)J recombination by interleukin-7. Journal of leukocyte biology 2001 Jun;69(6):907-11
  18. Huang J, Durum SK, Muegge K
    Cutting edge: histone acetylation and recombination at the TCR gamma locus follows IL-7 induction. Journal of immunology (Baltimore, Md. : 1950) 2001 Dec 1;167(11):6073-7
  19. Ye SK, Agata Y, Lee HC, Kurooka H, Kitamura T, Shimizu A, Honjo T, Ikuta K
    The IL-7 receptor controls the accessibility of the TCRgamma locus by Stat5 and histone acetylation. Immunity 2001 Nov;15(5):813-23
  20. Kuo TC, Schlissel MS
    Mechanisms controlling expression of the RAG locus during lymphocyte development. Current opinion in immunology 2009 Apr;21(2):173-8

  1. Kittipatarin C, Khaled AR
    Interlinking interleukin-7. Cytokine 2007 Jul;39(1):75-83
  2. Palmer MJ, Mahajan VS, Trajman LC, Irvine DJ, Lauffenburger DA, Chen J
    Interleukin-7 receptor signaling network: an integrated systems perspective. Cellular & molecular immunology 2008 Apr;5(2):79-89
  3. Johnston JA, Bacon CM, Finbloom DS, Rees RC, Kaplan D, Shibuya K, Ortaldo JR, Gupta S, Chen YQ, Giri JD
    Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15. Proceedings of the National Academy of Sciences of the United States of America 1995 Sep 12;92(19):8705-9
  4. Sharfe N, Dadi HK, Roifman CM
    JAK3 protein tyrosine kinase mediates interleukin-7-induced activation of phosphatidylinositol-3' kinase. Blood 1995 Sep 15;86(6):2077-85
  5. Benbernou N, Muegge K, Durum SK
    Interleukin (IL)-7 induces rapid activation of Pyk2, which is bound to Janus kinase 1 and IL-7Ralpha. The Journal of biological chemistry 2000 Mar 10;275(10):7060-5
  6. Rosenthal LA, Winestock KD, Finbloom DS
    IL-2 and IL-7 induce heterodimerization of STAT5 isoforms in human peripheral blood T lymphoblasts. Cellular immunology 1997 Nov 1;181(2):172-81
  7. Qin JZ, Kamarashev J, Zhang CL, Dummer R, Burg G, Döbbeling U
    Constitutive and interleukin-7- and interleukin-15-stimulated DNA binding of STAT and novel factors in cutaneous T cell lymphoma cells. The Journal of investigative dermatology 2001 Sep;117(3):583-9
  8. Gatzka M, Piekorz R, Moriggl R, Rawlings J, Ihle JN
    A role for STAT5A/B in protection of peripheral T-lymphocytes from postactivation apoptosis: insights from gene expression profiling. Cytokine 2006 May;34(3-4):143-54
  9. Cornish AL, Chong MM, Davey GM, Darwiche R, Nicola NA, Hilton DJ, Kay TW, Starr R, Alexander WS
    Suppressor of cytokine signaling-1 regulates signaling in response to interleukin-2 and other gamma c-dependent cytokines in peripheral T cells. The Journal of biological chemistry 2003 Jun 20;278(25):22755-61
  10. Ramanathan S, Gagnon J, Leblanc C, Rottapel R, Ilangumaran S
    Suppressor of cytokine signaling 1 stringently regulates distinct functions of IL-7 and IL-15 in vivo during T lymphocyte development and homeostasis. Journal of immunology (Baltimore, Md. : 1950) 2006 Apr 1;176(7):4029-41
  11. Johnston JA, Wang LM, Hanson EP, Sun XJ, White MF, Oakes SA, Pierce JH, O'Shea JJ
    Interleukins 2, 4, 7, and 15 stimulate tyrosine phosphorylation of insulin receptor substrates 1 and 2 in T cells. Potential role of JAK kinases. The Journal of biological chemistry 1995 Dec 1;270(48):28527-30
  12. Sharfe N, Roifman CM
    Differential association of phosphatidylinositol 3-kinase with insulin receptor substrate (IRS)-1 and IRS-2 in human thymocytes in response to IL-7. Journal of immunology (Baltimore, Md. : 1950) 1997 Aug 1;159(3):1107-14
  13. Venkitaraman AR, Cowling RJ
    Interleukin 7 receptor functions by recruiting the tyrosine kinase p59fyn through a segment of its cytoplasmic tail. Proceedings of the National Academy of Sciences of the United States of America 1992 Dec 15;89(24):12083-7
  14. Cantley LC
    The phosphoinositide 3-kinase pathway. Science (New York, N.Y.) 2002 May 31;296(5573):1655-7
  15. Abell K, Watson CJ
    The Jak/Stat pathway: a novel way to regulate PI3K activity. Cell cycle (Georgetown, Tex.) 2005 Jul;4(7):897-900
  16. Wofford JA, Wieman HL, Jacobs SR, Zhao Y, Rathmell JC
    IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. Blood 2008 Feb 15;111(4):2101-11
  17. Huang J, Muegge K
    Control of chromatin accessibility for V(D)J recombination by interleukin-7. Journal of leukocyte biology 2001 Jun;69(6):907-11
  18. Huang J, Durum SK, Muegge K
    Cutting edge: histone acetylation and recombination at the TCR gamma locus follows IL-7 induction. Journal of immunology (Baltimore, Md. : 1950) 2001 Dec 1;167(11):6073-7
  19. Ye SK, Agata Y, Lee HC, Kurooka H, Kitamura T, Shimizu A, Honjo T, Ikuta K
    The IL-7 receptor controls the accessibility of the TCRgamma locus by Stat5 and histone acetylation. Immunity 2001 Nov;15(5):813-23
  20. Kuo TC, Schlissel MS
    Mechanisms controlling expression of the RAG locus during lymphocyte development. Current opinion in immunology 2009 Apr;21(2):173-8

Target Details

Click on a target from the pathway image to view related information.