To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:2025
STAT5 inhibition leads to Suppression of STAT5 binding
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Inhibition of JAK3 leading to impairment of T-Cell Dependent Antibody Response||adjacent||High||High||Yasuhiro Yoshida (send email)||Under development: Not open for comment. Do not cite||Under Development|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Signal transducer and activator of transcription (STAT)5 phosphorylation induced Interleukin (IL)-2 receptor expression. Therefore the suppression of STAT5 phosphorylation interfere with IL-2 production after STAT5 DNA binding to promoter region.
Evidence Supporting this KER
STAT5a/ STAT5b/double knockout mice defects in IL-2-induced IL-2Rα expression suggesting that STAT5 is essential for that expression (25-Moriggl-1999,79-Kim-2001).
CD25 associates with the intermediate affinity IL-2Rβγ subunits to form the high affinity heterotrimeric IL-2Rαβγ. In response to ligation with IL-2, this complex signals through the IL-2Rβγ chains, resulting in phosphorylation of STAT5 (80-Waldmann-2006).
STAT5a/b mutant peripheral T cells in mice are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression. The STAT5 proteins are essential mediators of IL-2 signaling in T cells (31-Willerford-1995).
IL-2 binding to CD25 triggers the grouping with IL-2Rβ and γ-chains, thus leading to signal transduction through STAT5, mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinases (PI3K) (81-Remillard-1991,82-Ravichandran-1994,83-Fujii-1995). Within all T cell populations, IL-2 signaling appears to be primarily mediated through phosphorylation of STAT5 (84-Hirakawa-2016).
Upon T cell receptor (TCR) stimulation, IL-2/STAT5 signaling promotes T cell differentiation, which is the first key step to generating effector T cells that can target pathogens (85-Liao-2013).
Increasing the concentrations of IL-2 to superphysiological levels (1000 units/ml), which would eliminate the required upregulation of the IL-2 receptor α chain, also failed to induce a proliferative response with cells from Stat5a/b mutant mice (31-Willerford-1995).
Splenic lymphocytes from STAT5a/b, but not STAT5a or STAT5b, mutant mice failed to significantly respond to increasing concentrations of IL-2 in the presence of anti-CD3 (25-Moriggl-1999).
Uncertainties and Inconsistencies
Inhibition of phosphatase activity by calyculin A treatment of YT cells resulted in a significant induction of serine phosphorylation of JAK3 and STAT5, and serine/threonine phosphorylation of IL-2Rβ. Moreover, inhibition of Protein phosphatase 2 (PP2A) diminished IL-2-induced tyrosine phosphorylation of IL-2Rβ, JAK3, and STAT5, and abolished STAT5 DNA binding activity (86-Ross-2010).
Known modulating factors
At present, no evidence is found.
Known Feedforward/Feedback loops influencing this KER
IL-2 acts either on the same cell that secretes the cytokine, for instance, IL-2 produced by T cells operates on the same T cells that made it or on a nearby cell. With highest levels in secondary lymphoid organs, IL-2 is believed to act in an autocrine or paracrine manner to support effector and memory CD8 T cell differentiation (88-Kalia-2018).
Domain of Applicability
25. Moriggl, R., Topham, D. J., Teglund, S., Sexl, V., McKay, C., Wang, D., Hoffmeyer, A., van Deursen, J., Sangster, M. Y., Bunting, K. D., Grosveld, G. C., and Ihle, J. N. (1999) Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. Immunity 10, 249-259
31. Willerford, D. M., Chen, J., Ferry, J. A., Davidson, L., Ma, A., and Alt, F. W. (1995) Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3, 521-530
78. Zhang, H., Conrad, D. M., Butler, J. J., Zhao, C., Blay, J., and Hoskin, D. W. (2004) Adenosine acts through A2 receptors to inhibit IL-2-induced tyrosine phosphorylation of STAT5 in T lymphocytes: role of cyclic adenosine 3',5'-monophosphate and phosphatases. J Immunol 173, 932-944
79. Kim, H. P., Kelly, J., and Leonard, W. J. (2001) The basis for IL-2-induced IL-2 receptor alpha chain gene regulation: importance of two widely separated IL-2 response elements. Immunity 15, 159-172
80. Waldmann, T. A. (2006) The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol 6, 595-601
81. Remillard, B., Petrillo, R., Maslinski, W., Tsudo, M., Strom, T. B., Cantley, L., and Varticovski, L. (1991) Interleukin-2 receptor regulates activation of phosphatidylinositol 3-kinase. J Biol Chem 266, 14167-14170
82. Ravichandran, K. S., and Burakoff, S. J. (1994) The adapter protein Shc interacts with the interleukin-2 (IL-2) receptor upon IL-2 stimulation. J Biol Chem 269, 1599-1602
83. Fujii, H., Nakagawa, Y., Schindler, U., Kawahara, A., Mori, H., Gouilleux, F., Groner, B., Ihle, J. N., Minami, Y., Miyazaki, T., and et al. (1995) Activation of Stat5 by interleukin 2 requires a carboxyl-terminal region of the interleukin 2 receptor beta chain but is not essential for the proliferative signal transmission. Proc Natl Acad Sci U S A 92, 5482-5486
84. Hirakawa, M., Matos, T. R., Liu, H., Koreth, J., Kim, H. T., Paul, N. E., Murase, K., Whangbo, J., Alho, A. C., Nikiforow, S., Cutler, C., Ho, V. T., Armand, P., Alyea, E. P., Antin, J. H., Blazar, B. R., Lacerda, J. F., Soiffer, R. J., and Ritz, J. (2016) Low-dose IL-2 selectively activates subsets of CD4(+) Tregs and NK cells. JCI insight 1, e89278
85. Liao, W., Lin, J. X., and Leonard, W. J. (2013) Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 38, 13-25
86. Ross, J. A., Cheng, H., Nagy, Z. S., Frost, J. A., and Kirken, R. A. (2010) Protein phosphatase 2A regulates interleukin-2 receptor complex formation and JAK3/STAT5 activation. J Biol Chem 285, 3582-3591
87. Gonsky, R., Deem, R. L., Bream, J., Young, H. A., and Targan, S. R. (2004) Enhancer role of STAT5 in CD2 activation of IFN-gamma gene expression. J Immunol 173, 6241-6247
88. Kalia, V., and Sarkar, S. (2018) Regulation of Effector and Memory CD8 T Cell Differentiation by IL-2-A Balancing Act. Front Immunol 9, 2987