Immune response - IL-7 signaling in B lymphocytes

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IL-7 signaling in B lymphocytes

Interleukin 7 (IL-7) is an essential cytokine for the development and maintenance of B lymphocytes. Interleukin 7 receptor (IL-7 receptor), regulates lymphocyte survival, proliferation and differentiation [1], [2]. IL-7 receptor consists of two components, IL-7 receptor alpha chain (IL7RA) and a common gamma chain, Interleukin 2 receptor gamma (IL-2R gamma chain) [3].

IL-7 ligation to IL7RA results in its dimerization with IL-2R gamma chain and IL-7 receptor activation, which leads to subsequent tyrosine phosphorylation and activation of Janus kinases 1 and 3 (JAK1 and JAK3) [4], [5] and Src family tyrosine kinases FYN oncogene related to SRC (Fyn) [5], [6], and v-Yes-1 Yamaguchi sarcoma viral related oncogene homolog (Lyn) [7].

Active JAK1 and JAK3 induce phosphorylation of Signal transducers and activators of transcription 1, 3, and 5 (STAT1, STAT3 and STAT5) and their nuclear translocation [8], [9], [10]. STAT5 promotes transcription of target genes, expressing BCL2-like 1 (Bcl-XL), Pim-1 oncogene (Pim-1), and Cyclin D2. Bcl-XL leads to B-cells survival. Pim-1 and Cyclin D2 leads to cell proliferation [9].

In addition, IL-7 stimulates mitogen activated protein kinase ERK activation in B cells [11], [12], possibly, via JAK1/ Growth factor receptor-bound protein 2 (GRB2) / Son of sevenless homologues (SOS)/ V-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/ Harvey rat sarcoma viral oncogene homolog (H-Ras)/ Mitogen-activated protein kinase kinases 1 and 2 (MEK1 (MAP2K1) and MEK2 (MAP2K2) [13], [14]. IL-7-induced ERK stimulates cell proliferation [11], [12]

Phosphorylated JAKs and Src kinases induce Phosphoinositide-3-kinase regulatory subunit 1alpha (PI3K reg class IA (p85-alpha)), which activates Phosphoinositide-3-kinase catalytic alpha polypeptide (PI3K cat class IA (p 110-alpha)) that leads to Phosphatidylinositol(3,4,5) triphosphate (PtdIns(3,4,5)P3) conversion from PtdIns(4,5)P2. PtdIns(3,4,5)P3 in turn induces Akt(PKB) and 3-phosphoinositide dependent protein kinase-1 (PDK (PDPK1)) activation that promotes lymphocytes proliferation.

IL-7 stimulates V(D)J recombination of Immunoglobulin H (Igh) in B 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 [15]. IL-7 receptor signaling cause up regulation of the transcription factors Early B-cell factor 1 (EBF) in STAT5-, Paired box 5 (PAX5) and Transcription factor 3 (E2A)-dependent manner [16], [17], [18]. STAT5 functions at a distinct step in distal Immunoglobulin H (Igh) recombination in relation to Pax5, EBF and Oct-1 [19]. E2A stimulate expression of N-Myc activating B cell proliferation [20].

In addition, Akt(PKB) activation serves for Forkhead boxes O1 (FKHR) negative control. It leads to inhibition of FKHR-dependent transcription Recombination activating gene 1 and 2 (RAG1 and RAG2) stimulating B cell differentiation. The RAG1/ RAG2 dimer recognizes the synapsis formed by the recognition motifs and initiates the cleavage step of V(D)J recombination [21].

After IL-7 promotes immunoglobulin gene rearrangement, pre-B cell receptor (pre-BCR) decreases expression of the IL7RA and responsiveness of pre-B cells to IL-7 signals [1], [22].

References:

  1. Fry TJ, Mackall CL
    Interleukin-7: from bench to clinic. Blood 2002 Jun 1;99(11):3892-904
  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. Jiang Q, Li WQ, Aiello FB, Mazzucchelli R, Asefa B, Khaled AR, Durum SK
    Cell biology of IL-7, a key lymphotrophin. Cytokine & growth factor reviews 2005 Aug-Oct;16(4-5):513-33
  4. 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
  5. Cosenza L, Gorgun G, Urbano A, Foss F
    Interleukin-7 receptor expression and activation in nonhaematopoietic neoplastic cell lines. Cellular signalling 2002 Apr;14(4):317-25
  6. 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
  7. Seckinger P, Fougereau M
    Activation of src family kinases in human pre-B cells by IL-7. Journal of immunology (Baltimore, Md. : 1950) 1994 Jul 1;153(1):97-109
  8. van der Plas DC, Smiers F, Pouwels K, Hoefsloot LH, Löwenberg B, Touw IP
    Interleukin-7 signaling in human B cell precursor acute lymphoblastic leukemia cells and murine BAF3 cells involves activation of STAT1 and STAT5 mediated via the interleukin-7 receptor alpha chain. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 1996 Aug;10(8):1317-25
  9. Goetz CA, Harmon IR, O'Neil JJ, Burchill MA, Farrar MA
    STAT5 activation underlies IL7 receptor-dependent B cell development. Journal of immunology (Baltimore, Md. : 1950) 2004 Apr 15;172(8):4770-8
  10. Chou WC, Levy DE, Lee CK
    STAT3 positively regulates an early step in B-cell development. Blood 2006 Nov 1;108(9):3005-11
  11. Fleming HE, Paige CJ
    Pre-B cell receptor signaling mediates selective response to IL-7 at the pro-B to pre-B cell transition via an ERK/MAP kinase-dependent pathway. Immunity 2001 Oct;15(4):521-31
  12. Johnson SE, Shah N, Bajer AA, LeBien TW
    IL-7 activates the phosphatidylinositol 3-kinase/AKT pathway in normal human thymocytes but not normal human B cell precursors. Journal of immunology (Baltimore, Md. : 1950) 2008 Jun 15;180(12):8109-17
  13. Postel-Vinay MC, Kelly PA
    Growth hormone receptor signalling. Bailliere's clinical endocrinology and metabolism 1996 Jul;10(3):323-36
  14. Weinstein-Oppenheimer CR, Blalock WL, Steelman LS, Chang F, McCubrey JA
    The Raf signal transduction cascade as a target for chemotherapeutic intervention in growth factor-responsive tumors. Pharmacology & therapeutics 2000 Dec;88(3):229-79
  15. Fugmann SD, Lee AI, Shockett PE, Villey IJ, Schatz DG
    The RAG proteins and V(D)J recombination: complexes, ends, and transposition. Annual review of immunology 2000;18:495-527
  16. Hirokawa S, Sato H, Kato I, Kudo A
    EBF-regulating Pax5 transcription is enhanced by STAT5 in the early stage of B cells. European journal of immunology 2003 Jul;33(7):1824-9
  17. Kikuchi K, Lai AY, Hsu CL, Kondo M
    IL-7 receptor signaling is necessary for stage transition in adult B cell development through up-regulation of EBF. The Journal of experimental medicine 2005 Apr 18;201(8):1197-203
  18. Roessler S, Györy I, Imhof S, Spivakov M, Williams RR, Busslinger M, Fisher AG, Grosschedl R
    Distinct promoters mediate the regulation of Ebf1 gene expression by interleukin-7 and Pax5. Molecular and cellular biology 2007 Jan;27(2):579-94
  19. Bertolino E, Reddy K, Medina KL, Parganas E, Ihle J, Singh H
    Regulation of interleukin 7-dependent immunoglobulin heavy-chain variable gene rearrangements by transcription factor STAT5. Nature immunology 2005 Aug;6(8):836-43
  20. Seet CS, Brumbaugh RL, Kee BL
    Early B cell factor promotes B lymphopoiesis with reduced interleukin 7 responsiveness in the absence of E2A. The Journal of experimental medicine 2004 Jun 21;199(12):1689-700
  21. Amin RH, Schlissel MS
    Foxo1 directly regulates the transcription of recombination-activating genes during B cell development. Nature immunology 2008 Jun;9(6):613-22
  22. Schebesta M, Pfeffer PL, Busslinger M
    Control of pre-BCR signaling by Pax5-dependent activation of the BLNK gene. Immunity 2002 Oct;17(4):473-85

  1. Fry TJ, Mackall CL
    Interleukin-7: from bench to clinic. Blood 2002 Jun 1;99(11):3892-904
  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. Jiang Q, Li WQ, Aiello FB, Mazzucchelli R, Asefa B, Khaled AR, Durum SK
    Cell biology of IL-7, a key lymphotrophin. Cytokine & growth factor reviews 2005 Aug-Oct;16(4-5):513-33
  4. 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
  5. Cosenza L, Gorgun G, Urbano A, Foss F
    Interleukin-7 receptor expression and activation in nonhaematopoietic neoplastic cell lines. Cellular signalling 2002 Apr;14(4):317-25
  6. 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
  7. Seckinger P, Fougereau M
    Activation of src family kinases in human pre-B cells by IL-7. Journal of immunology (Baltimore, Md. : 1950) 1994 Jul 1;153(1):97-109
  8. van der Plas DC, Smiers F, Pouwels K, Hoefsloot LH, Löwenberg B, Touw IP
    Interleukin-7 signaling in human B cell precursor acute lymphoblastic leukemia cells and murine BAF3 cells involves activation of STAT1 and STAT5 mediated via the interleukin-7 receptor alpha chain. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 1996 Aug;10(8):1317-25
  9. Goetz CA, Harmon IR, O'Neil JJ, Burchill MA, Farrar MA
    STAT5 activation underlies IL7 receptor-dependent B cell development. Journal of immunology (Baltimore, Md. : 1950) 2004 Apr 15;172(8):4770-8
  10. Chou WC, Levy DE, Lee CK
    STAT3 positively regulates an early step in B-cell development. Blood 2006 Nov 1;108(9):3005-11
  11. Fleming HE, Paige CJ
    Pre-B cell receptor signaling mediates selective response to IL-7 at the pro-B to pre-B cell transition via an ERK/MAP kinase-dependent pathway. Immunity 2001 Oct;15(4):521-31
  12. Johnson SE, Shah N, Bajer AA, LeBien TW
    IL-7 activates the phosphatidylinositol 3-kinase/AKT pathway in normal human thymocytes but not normal human B cell precursors. Journal of immunology (Baltimore, Md. : 1950) 2008 Jun 15;180(12):8109-17
  13. Postel-Vinay MC, Kelly PA
    Growth hormone receptor signalling. Bailliere's clinical endocrinology and metabolism 1996 Jul;10(3):323-36
  14. Weinstein-Oppenheimer CR, Blalock WL, Steelman LS, Chang F, McCubrey JA
    The Raf signal transduction cascade as a target for chemotherapeutic intervention in growth factor-responsive tumors. Pharmacology & therapeutics 2000 Dec;88(3):229-79
  15. Fugmann SD, Lee AI, Shockett PE, Villey IJ, Schatz DG
    The RAG proteins and V(D)J recombination: complexes, ends, and transposition. Annual review of immunology 2000;18:495-527
  16. Hirokawa S, Sato H, Kato I, Kudo A
    EBF-regulating Pax5 transcription is enhanced by STAT5 in the early stage of B cells. European journal of immunology 2003 Jul;33(7):1824-9
  17. Kikuchi K, Lai AY, Hsu CL, Kondo M
    IL-7 receptor signaling is necessary for stage transition in adult B cell development through up-regulation of EBF. The Journal of experimental medicine 2005 Apr 18;201(8):1197-203
  18. Roessler S, Györy I, Imhof S, Spivakov M, Williams RR, Busslinger M, Fisher AG, Grosschedl R
    Distinct promoters mediate the regulation of Ebf1 gene expression by interleukin-7 and Pax5. Molecular and cellular biology 2007 Jan;27(2):579-94
  19. Bertolino E, Reddy K, Medina KL, Parganas E, Ihle J, Singh H
    Regulation of interleukin 7-dependent immunoglobulin heavy-chain variable gene rearrangements by transcription factor STAT5. Nature immunology 2005 Aug;6(8):836-43
  20. Seet CS, Brumbaugh RL, Kee BL
    Early B cell factor promotes B lymphopoiesis with reduced interleukin 7 responsiveness in the absence of E2A. The Journal of experimental medicine 2004 Jun 21;199(12):1689-700
  21. Amin RH, Schlissel MS
    Foxo1 directly regulates the transcription of recombination-activating genes during B cell development. Nature immunology 2008 Jun;9(6):613-22
  22. Schebesta M, Pfeffer PL, Busslinger M
    Control of pre-BCR signaling by Pax5-dependent activation of the BLNK gene. Immunity 2002 Oct;17(4):473-85

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