Immune response - CD137 signaling in immune cell

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CD137 signaling in immune cell

CD137(TNFRSF9) is an inducible T cell surface receptor belonging to the tumor necrosis factor receptor superfamily. It presents on the surfaces of activated CD4+ and CD8+ T cells, monocytes and B lymphocytes. CD137(TNFRSF9) signaling is activated by binding to its high-affinity ligand CD137 ligand(TNFSF9) expressed on the antigen-presenting cell surface. CD137(TNFRSF9) signaling promotes cell growth, T cell differentiation and survival (see anti-apoptosis of immune cells [1], [2].

CD137(TNFRSF9) mediates its action via association with TRAF1 and TRAF2. CD137(TNFRSF9) binding to TRAF2 leads to activation of the NIK(MAP3K14). NIK(MAP3K14) activates NF-kB via the IKK-alpha/ NFKBIA pathway [2], [3], [4]. NF-kB induces transcription of Bcl-XL, Bcl-2 and BFL1, and thus promotes survival (see anti-apoptosis of immune cells [5], [6], [7].

In addition, activation of NF-kB stimulates expression of IL-2, IL-4 and IFN-gamma [2], [8].

CD137(TNFRSF9) binding to TRAF2 also promotes activation of the ASK1 (MAP3K5). ASK1 (MAP3K5) induces JNK1(MAPK8) and p38 MAPK activation via MEK3(MAP2K3), MEK4(MAP2K4) and MEK6(MAP2K6). JNK1(MAPK8) and p38 MAPK phosphorylate ATF-2 and c-Jun. Activation of ATF-2 and c-Jun also induces production of IL-2, IL-4 and IFN-gamma and leads to Th1 and Th2 cell development (see T-helper cell differentiation [9], [10].

Also, CD137(TNFRSF9) association with TRAF1 and TRAF2 leads to ERK1/2 activation via TRAF1 stimulation of ERK1/2 activity and possible TRAF2/ NIK(MAP3K14)/ MEKK1(MAP3K1)/ MEK1(MAP2K1) pathway [7], [11], [12], [13]. ERK1/2 activation leads to Cyclin D2 transcription possibly via c-Jun. In addition, CD137(TNFRSF9)-induced IL-2 signaling triggers translation of Cyclin D2 protein [7], [14]. Cyclin D2 stimulates expression of Cyclin E and this leads to cell cycle progression (see positive regulation of cell cycle) and promotes cell proliferation of CD4-positive and CD8-positive cells under CD137(TNFRSF9) control [11], [14], [15], [16], [17], [18], [19].

CD137(TNFRSF9)-induced ERK1/2 activation also leads to Bim phosphorylation by ERK1/2. It promotes proteosomal degradation of Bim and leads to immune cell survival [13], [19].



Objects list:

ASK1 (MAP3K5) Mitogen-activated protein kinase kinase kinase 5
ATF-2 Cyclic AMP-dependent transcription factor ATF-2
BFL1 Bcl-2-related protein A1
Bcl-2 Apoptosis regulator Bcl-2
Bcl-XL Bcl-2-like protein 1
Bim Bcl-2-like protein 11
CD137 ligand(TNFSF9) Tumor necrosis factor ligand superfamily member 9
CD137(TNFRSF9) Tumor necrosis factor receptor superfamily member 9
Cyclin D2 G1/S-specific cyclin-D2
Cyclin E G1/S-specific cyclin-E1
ERK1/2 Erk 1/2 Protein group
IFN-gamma Interferon gamma
IKK-alpha Inhibitor of nuclear factor kappa-B kinase subunit alpha
IL-2 Interleukin-2
IL-4 Interleukin-4
JNK1(MAPK8) Mitogen-activated protein kinase 8
MEK1(MAP2K1) Dual specificity mitogen-activated protein kinase kinase 1
MEK3(MAP2K3) Dual specificity mitogen-activated protein kinase kinase 3
MEK4(MAP2K4) Dual specificity mitogen-activated protein kinase kinase 4
MEK6(MAP2K6) Dual specificity mitogen-activated protein kinase kinase 6
MEKK1(MAP3K1) Mitogen-activated protein kinase kinase kinase 1
NF-kB NF-kB Group of complexes
NFKBIA NF-kappa-B inhibitor alpha
NIK(MAP3K14) Mitogen-activated protein kinase kinase kinase 14
TRAF1 TNF receptor-associated factor 1
TRAF2 TNF receptor-associated factor 2
c-Jun Transcription factor AP-1
p38 MAPK p38 mitogen-activated protein kinase Protein group

References:

  1. Wang HR, Kania M, Baumeister W, Nederlof PM
    Import of human and Thermoplasma 20S proteasomes into nuclei of HeLa cells requires functional NLS sequences. European journal of cell biology 1997 Jun;73(2):105-13
  2. Vinay DS, Kwon BS
    Role of 4-1BB in immune responses. Seminars in immunology 1998 Dec;10(6):481-9
  3. Arch RH, Thompson CB
    4-1BB and Ox40 are members of a tumor necrosis factor (TNF)-nerve growth factor receptor subfamily that bind TNF receptor-associated factors and activate nuclear factor kappaB. Molecular and cellular biology 1998 Jan;18(1):558-65
  4. Jang IK, Lee ZH, Kim YJ, Kim SH, Kwon BS
    Human 4-1BB (CD137) signals are mediated by TRAF2 and activate nuclear factor-kappa B. Biochemical and biophysical research communications 1998 Jan 26;242(3):613-20
  5. Stergachis A
    Roles for pharmacists in the prevention and control of sexually transmitted diseases. Sexually transmitted diseases 1999 Apr;26(4 Suppl):S44-7; discussion S48
  6. Lee HW, Park SJ, Choi BK, Kim HH, Nam KO, Kwon BS
    4-1BB promotes the survival of CD8+ T lymphocytes by increasing expression of Bcl-xL and Bfl-1. Journal of immunology (Baltimore, Md. : 1950) 2002 Nov 1;169(9):4882-8
  7. Lee HW, Nam KO, Seo SK, Kim YH, Kang H, Kwon BS
    4-1BB cross-linking enhances the survival and cell cycle progression of CD4 T lymphocytes. Cellular immunology 2003 Jun;223(2):143-50
  8. Saoulli K, Lee SY, Cannons JL, Yeh WC, Santana A, Goldstein MD, Bangia N, DeBenedette MA, Mak TW, Choi Y, Watts TH
    CD28-independent, TRAF2-dependent costimulation of resting T cells by 4-1BB ligand. The Journal of experimental medicine 1998 Jun 1;187(11):1849-62
  9. Cannons JL, Hoeflich KP, Woodgett JR, Watts TH
    Role of the stress kinase pathway in signaling via the T cell costimulatory receptor 4-1BB. Journal of immunology (Baltimore, Md. : 1950) 1999 Sep 15;163(6):2990-8
  10. Cannons JL, Choi Y, Watts TH
    Role of TNF receptor-associated factor 2 and p38 mitogen-activated protein kinase activation during 4-1BB-dependent immune response. Journal of immunology (Baltimore, Md. : 1950) 2000 Dec 1;165(11):6193-204
  11. Yujiri T, Sather S, Fanger GR, Johnson GL
    Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption. Science (New York, N.Y.) 1998 Dec 4;282(5395):1911-4
  12. Uche UE, Jones TW
    Complement (C3) levels and activation in rabbits experimentally infected with Trypanosoma evansi. Annals of tropical medicine and parasitology 1992 Oct;86(5):475-80
  13. Sabbagh L, Pulle G, Liu Y, Tsitsikov EN, Watts TH
    ERK-dependent Bim modulation downstream of the 4-1BB-TRAF1 signaling axis is a critical mediator of CD8 T cell survival in vivo. Journal of immunology (Baltimore, Md. : 1950) 2008 Jun 15;180(12):8093-101
  14. Lee HW, Nam KO, Park SJ, Kwon BS
    4-1BB enhances CD8+ T cell expansion by regulating cell cycle progression through changes in expression of cyclins D and E and cyclin-dependent kinase inhibitor p27kip1. European journal of immunology 2003 Aug;33(8):2133-41
  15. Shuford WW, Klussman K, Tritchler DD, Loo DT, Chalupny J, Siadak AW, Brown TJ, Emswiler J, Raecho H, Larsen CP, Pearson TC, Ledbetter JA, Aruffo A, Mittler RS
    4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses. The Journal of experimental medicine 1997 Jul 7;186(1):47-55
  16. Cannons JL, Lau P, Ghumman B, DeBenedette MA, Yagita H, Okumura K, Watts TH
    4-1BB ligand induces cell division, sustains survival, and enhances effector function of CD4 and CD8 T cells with similar efficacy. Journal of immunology (Baltimore, Md. : 1950) 2001 Aug 1;167(3):1313-24
  17. Bertram EM, Lau P, Watts TH
    Temporal segregation of 4-1BB versus CD28-mediated costimulation: 4-1BB ligand influences T cell numbers late in the primary response and regulates the size of the T cell memory response following influenza infection. Journal of immunology (Baltimore, Md. : 1950) 2002 Apr 15;168(8):3777-85
  18. Kwon BS, Hurtado JC, Lee ZH, Kwack KB, Seo SK, Choi BK, Koller BH, Wolisi G, Broxmeyer HE, Vinay DS
    Immune responses in 4-1BB (CD137)-deficient mice. Journal of immunology (Baltimore, Md. : 1950) 2002 Jun 1;168(11):5483-90
  19. Laderach D, Movassagh M, Johnson A, Mittler RS, Galy A
    4-1BB co-stimulation enhances human CD8(+) T cell priming by augmenting the proliferation and survival of effector CD8(+) T cells. International immunology 2002 Oct;14(10):1155-67

  1. Wang HR, Kania M, Baumeister W, Nederlof PM
    Import of human and Thermoplasma 20S proteasomes into nuclei of HeLa cells requires functional NLS sequences. European journal of cell biology 1997 Jun;73(2):105-13
  2. Vinay DS, Kwon BS
    Role of 4-1BB in immune responses. Seminars in immunology 1998 Dec;10(6):481-9
  3. Arch RH, Thompson CB
    4-1BB and Ox40 are members of a tumor necrosis factor (TNF)-nerve growth factor receptor subfamily that bind TNF receptor-associated factors and activate nuclear factor kappaB. Molecular and cellular biology 1998 Jan;18(1):558-65
  4. Jang IK, Lee ZH, Kim YJ, Kim SH, Kwon BS
    Human 4-1BB (CD137) signals are mediated by TRAF2 and activate nuclear factor-kappa B. Biochemical and biophysical research communications 1998 Jan 26;242(3):613-20
  5. Stergachis A
    Roles for pharmacists in the prevention and control of sexually transmitted diseases. Sexually transmitted diseases 1999 Apr;26(4 Suppl):S44-7; discussion S48
  6. Lee HW, Park SJ, Choi BK, Kim HH, Nam KO, Kwon BS
    4-1BB promotes the survival of CD8+ T lymphocytes by increasing expression of Bcl-xL and Bfl-1. Journal of immunology (Baltimore, Md. : 1950) 2002 Nov 1;169(9):4882-8
  7. Lee HW, Nam KO, Seo SK, Kim YH, Kang H, Kwon BS
    4-1BB cross-linking enhances the survival and cell cycle progression of CD4 T lymphocytes. Cellular immunology 2003 Jun;223(2):143-50
  8. Saoulli K, Lee SY, Cannons JL, Yeh WC, Santana A, Goldstein MD, Bangia N, DeBenedette MA, Mak TW, Choi Y, Watts TH
    CD28-independent, TRAF2-dependent costimulation of resting T cells by 4-1BB ligand. The Journal of experimental medicine 1998 Jun 1;187(11):1849-62
  9. Cannons JL, Hoeflich KP, Woodgett JR, Watts TH
    Role of the stress kinase pathway in signaling via the T cell costimulatory receptor 4-1BB. Journal of immunology (Baltimore, Md. : 1950) 1999 Sep 15;163(6):2990-8
  10. Cannons JL, Choi Y, Watts TH
    Role of TNF receptor-associated factor 2 and p38 mitogen-activated protein kinase activation during 4-1BB-dependent immune response. Journal of immunology (Baltimore, Md. : 1950) 2000 Dec 1;165(11):6193-204
  11. Yujiri T, Sather S, Fanger GR, Johnson GL
    Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption. Science (New York, N.Y.) 1998 Dec 4;282(5395):1911-4
  12. Uche UE, Jones TW
    Complement (C3) levels and activation in rabbits experimentally infected with Trypanosoma evansi. Annals of tropical medicine and parasitology 1992 Oct;86(5):475-80
  13. Sabbagh L, Pulle G, Liu Y, Tsitsikov EN, Watts TH
    ERK-dependent Bim modulation downstream of the 4-1BB-TRAF1 signaling axis is a critical mediator of CD8 T cell survival in vivo. Journal of immunology (Baltimore, Md. : 1950) 2008 Jun 15;180(12):8093-101
  14. Lee HW, Nam KO, Park SJ, Kwon BS
    4-1BB enhances CD8+ T cell expansion by regulating cell cycle progression through changes in expression of cyclins D and E and cyclin-dependent kinase inhibitor p27kip1. European journal of immunology 2003 Aug;33(8):2133-41
  15. Shuford WW, Klussman K, Tritchler DD, Loo DT, Chalupny J, Siadak AW, Brown TJ, Emswiler J, Raecho H, Larsen CP, Pearson TC, Ledbetter JA, Aruffo A, Mittler RS
    4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses. The Journal of experimental medicine 1997 Jul 7;186(1):47-55
  16. Cannons JL, Lau P, Ghumman B, DeBenedette MA, Yagita H, Okumura K, Watts TH
    4-1BB ligand induces cell division, sustains survival, and enhances effector function of CD4 and CD8 T cells with similar efficacy. Journal of immunology (Baltimore, Md. : 1950) 2001 Aug 1;167(3):1313-24
  17. Bertram EM, Lau P, Watts TH
    Temporal segregation of 4-1BB versus CD28-mediated costimulation: 4-1BB ligand influences T cell numbers late in the primary response and regulates the size of the T cell memory response following influenza infection. Journal of immunology (Baltimore, Md. : 1950) 2002 Apr 15;168(8):3777-85
  18. Kwon BS, Hurtado JC, Lee ZH, Kwack KB, Seo SK, Choi BK, Koller BH, Wolisi G, Broxmeyer HE, Vinay DS
    Immune responses in 4-1BB (CD137)-deficient mice. Journal of immunology (Baltimore, Md. : 1950) 2002 Jun 1;168(11):5483-90
  19. Laderach D, Movassagh M, Johnson A, Mittler RS, Galy A
    4-1BB co-stimulation enhances human CD8(+) T cell priming by augmenting the proliferation and survival of effector CD8(+) T cells. International immunology 2002 Oct;14(10):1155-67

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