Overview
IL7 receptor signaling in T cells: A mathematical modeling perspective
Jung-Hyun Park,
Adam T. Waickman,
Joseph Reynolds,
Mario Castro,
Carmen Molina-París,
Jung-Hyun Park
Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, Maryland
Search for more papers by this authorAdam T. Waickman
Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, Maryland
Search for more papers by this authorJoseph Reynolds
Safety and Environmental Assurance Centre (SEAC), Unilever, UK
Search for more papers by this authorMario Castro
Universidad Pontificia Comillas, GISC and DNL, Madrid, Spain
Department of Applied Mathematics, School of Mathematics, University of Leeds, Leeds, UK
Search for more papers by this authorCorresponding Author
Carmen Molina-París
Department of Applied Mathematics, School of Mathematics, University of Leeds, Leeds, UK
Correspondence
Carmen Molina-París, Department of Applied Mathematics, School of Mathematics, University of Leeds, Leeds, UK.
Email: [email protected]
Search for more papers by this authorJung-Hyun Park,
Adam T. Waickman,
Joseph Reynolds,
Mario Castro,
Carmen Molina-París,
Jung-Hyun Park
Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, Maryland
Search for more papers by this authorAdam T. Waickman
Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, Maryland
Search for more papers by this authorJoseph Reynolds
Safety and Environmental Assurance Centre (SEAC), Unilever, UK
Search for more papers by this authorMario Castro
Universidad Pontificia Comillas, GISC and DNL, Madrid, Spain
Department of Applied Mathematics, School of Mathematics, University of Leeds, Leeds, UK
Search for more papers by this authorCorresponding Author
Carmen Molina-París
Department of Applied Mathematics, School of Mathematics, University of Leeds, Leeds, UK
Correspondence
Carmen Molina-París, Department of Applied Mathematics, School of Mathematics, University of Leeds, Leeds, UK.
Email: [email protected]
Search for more papers by this authorFunding information European Union FP7 Programme, Grant/Award Number: PIRSES-GA-2012-317893; European Union H2020 Programme, Grant/Award Number: 764698 MSCA-ITN-2017 (QuanTII ETN); Spanish Ministry of Economy, Grant/Award Numbers: FIS2016-78883-C2-2-P, PRX 16/00287
Abstract
Interleukin-7 (IL7) plays a nonredundant role in T cell survival and homeostasis, which is illustrated in the severe T cell lymphopenia of IL7-deficient mice, or demonstrated in animals or humans that lack expression of either the IL7Rα or γ c chain, the two subunits that constitute the functional IL7 receptor. Remarkably, IL7 is not expressed by T cells themselves, but produced in limited amounts by radio-resistant stromal cells. Thus, T cells need to constantly compete for IL7 to survive. How T cells maintain homeostasis and further maximize the size of the peripheral T cell pool in face of such competition are important questions that have fascinated both immunologists and mathematicians for a long time. Exceptionally, IL7 downregulates expression of its own receptor, so that IL7-signaled T cells do not consume extracellular IL7, and thus, the remaining extracellular IL7 can be shared among unsignaled T cells. Such an altruistic behavior of the IL7Rα chain is quite unique among members of the γ c cytokine receptor family. However, the consequences of this altruistic signaling behavior at the molecular, single cell and population levels are less well understood and require further investigation. In this regard, mathematical modeling of how a limited resource can be shared, while maintaining the clonal diversity of the T cell pool, can help decipher the molecular or cellular mechanisms that regulate T cell homeostasis. Thus, the current review aims to provide a mathematical modeling perspective of IL7-dependent T cell homeostasis at the molecular, cellular and population levels, in the context of recent advances in our understanding of the IL7 biology.
This article is categorized under:
- Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models
- Biological Mechanisms > Cell Signaling
- Models of Systems Properties and Processes > Mechanistic Models
- Analytical and Computational Methods > Computational Methods
CONFLICT OF INTEREST
The authors have declared no conflicts of interest for this article.
REFERENCES
- Abe, A., Tani-ichi, S., Shitara, S., Cui, G., Yamada, H., Miyachi, H., … Ikuta, K. (2015). An enhancer of the il-7 receptor α-chain locus controls il-7 receptor expression and maintenance of peripheral t cells. The Journal of Immunology, 195(7), 3129–3138.
- Akashi, K., Kondo, M., von Freeden-Jeffry, U., Murray, R., & Weissman, I. L. (1997). Bcl-2 rescues t lymphopoiesis in interleukin-7 receptor–deficient mice. Cell, 89(7), 1033–1041.
- Blinov, M. L., Faeder, J. R., Goldstein, B., & Hlavacek, W. S. (2004). Bionetgen: Software for rule-based modeling of signal transduction based on the interactions of molecular domains. Bioinformatics, 20(17), 3289–3291.
- Busse, D., de la Rosa, M., Hobiger, K., Thurley, K., Flossdorf, M., Scheffold, A., & Höfer, T. (2010). Competing feedback loops shape il-2 signaling between helper and regulatory t lymphocytes in cellular microenvironments. Proceedings of the National Academy of Sciences of the United States of America, 107(7), 3058–3063.
- Callard, R., George, A. J. T., & Stark, J. (1999). Cytokines, chaos, and complexity. Immunity, 11(5), 507–513.
- Castro, M., Lythe, G., & Molina-París, C. (2017). The t cells in an ageing virtual mouse. In Stochastic processes, multiscale modeling, and numerical methods for computational cellular biology (pp. 127–140). New York: Springer.
- Castro, M., Lythe, G., Molina-París, C., & Ribeiro, R. M. (2016). Mathematics in modern immunology. Interface Focus, 6(2), 20150093.
- Chong, M. M. W., Cornish, A. L., Darwiche, R., Stanley, E. G., Purton, J. F., Godfrey, D. I., … Kay, T. W. H. (2003). Suppressor of cytokine signaling-1 is a critical regulator of interleukin-7-dependent cd8+ t cell differentiation. Immunity, 18(4), 475–487.
- Cotari, J. W., Voisinne, G., Dar, O. E., Karabacak, V., & Altan-Bonnet, G. (2013). Cell-to-cell variability analysis dissects the plasticity of signaling of common γ chain cytokines in t cells. Science Signaling, 6(266), ra17–ra17.
- de la Higuera, L., López-García, M., Lythe, G., & Molina-París, C. (2017). Il-2 stimulation of regulatory t cells: A stochastic and algorithmic approach. In Modeling cellular systems (pp. 81–105). New York: Springer.
- DeKoter, R. P., Lee, H.-J., & Singh, H. (2002). Pu. 1 regulates expression of the interleukin-7 receptor in lymphoid progenitors. Immunity, 16(2), 297–309.
- Depper, J. M., Leonard, W. J., Drogula, C., Krönke, M., Waldmann, T. A., & Greene, W. C. (1985). Interleukin 2 (il-2) augments transcription of the il-2 receptor gene. Proceedings of the National Academy of Sciences of the United States of America, 82(12), 4230–4234.
- Dooms, H. (2013). Interleukin-7: Fuel for the autoimmune attack. Journal of Autoimmunity, 45, 40–48.
- Durum, S. K. (2014). Il-7 and tslp receptors: Twisted sisters. Blood, 124(1), 4–5.
- Faeder, J. R., Blinov, M. L., & Hlavacek, W. S. (2009). Rule-based modeling of biochemical systems with bionetgen. Systems Biology, 500, 113–167.
- Faller, E. M., Ghazawi, F. M., Cavar, M., & MacPherson, P. A. (2016). Il-7 induces clathrin-mediated endocytosis of cd127 and subsequent degradation by the proteasome in primary human cd8 t cells. Immunology and Cell Biology, 94(2), 196–207.
- Fallon, E. M., & Lauffenburger, D. A. (2000). Computational model for effects of ligand/receptor binding properties on interleukin-2 trafficking dynamics and t cell proliferation response. Biotechnology Progress, 16(5), 905–916.
- Feinerman, O., Jentsch, G., Tkach, K. E., Coward, J. W., Hathorn, M. M., Sneddon, M. W., … Altan-Bonnet, G. (2010). Single-cell quantification of il-2 response by effector and regulatory t cells reveals critical plasticity in immune response. Molecular Systems Biology, 6(1), 437.
- Feng, X., Wang, H., Takata, H., Day, T. J., Willen, J., & Hu, H. (2011). Transcription factor foxp1 exerts essential cell-intrinsic regulation of the quiescence of naive t cells. Nature Immunology, 12(6), 544–550.
- Fredriksson, S., Gullberg, M., Jarvius, J., Olsson, C., Pietras, K., Gústafsdóttir, S. M., … Landegren, U. (2002). Protein detection using proximity-dependent dna ligation assays. Nature Biotechnology, 20(5), 473–477.
- Freed, D. M., Bessman, N. J., Kiyatkin, A., Salazar-Cavazos, E., Byrne, P. O., Moore, J. O., … Lemmon, M. A. (2017). Egfr ligands differentially stabilize receptor dimers to specify signaling kinetics. Cell, 171(3), 683–695.
- Friedrich, C., & Gasteiger, G. (2017). Ilcs and t cells competing for space: More than a numbers game. Immunity, 47(1), 8–10.
- Fry, T. J., Connick, E., Falloon, J., Lederman, M. M., Liewehr, D. J., Spritzler, J., … Mackall, C. L. (2001). A potential role for interleukin-7 in t-cell homeostasis. Blood, 97(10), 2983–2990.
- Fry, T. J., & Mackall, C. L. (2002). Interleukin-7: From bench to clinic. Blood, 99(11), 3892–3904.
- Gonnord, P., Angermann, B. R., Sadtler, K., Gombos, E., Chappert, P., Meier-Schellersheim, M., & Varma, R. (2018). A hierarchy of affinities between cytokine receptors and the common gamma chain leads to pathway cross-talk. Science Signaling, 11(524), eaal1253.
- Henriques, C. M., Rino, J., Nibbs, R. J., Graham, G. J., & Barata, J. T. (2010). Il-7 induces rapid clathrin-mediated internalization and jak3-dependent degradation of il-7rα in t cells. Blood, 115(16), 3269–3277.
- Hong, C., Luckey, M. A., Ligons, D. L., Waickman, A. T., Park, J.-Y., Kim, G. Y., … Park, J.-H. (2014). Activated t cells secrete an alternatively spliced form of common γ-chain that inhibits cytokine signaling and exacerbates inflammation. Immunity, 40(6), 910–923.
- Jiang, Q., Li, W. Q., Hofmeister, R. R., Young, H. A., Hodge, D. R., Keller, J. R., … Durum, S. K. (2004). Distinct regions of the interleukin-7 receptor regulate different bcl2 family members. Molecular and Cellular Biology, 24(14), 6501–6513.
- Katz, G., Pobezinsky, L. A., Jeurling, S., Shinzawa, M., Van Laethem, F., & Singer, A. (2014). T cell receptor stimulation impairs il-7 receptor signaling by inducing expression of the microrna mir-17 to target janus kinase 1. Science Signaling, 7(340), ra83–ra83.
- Kerdiles, Y. M., Beisner, D. R., Tinoco, R., Dejean, A. S., Castrillon, D. H., DePinho, R. A., & Hedrick, S. M. (2009). Foxo1 links homing and survival of naive t cells by regulating l-selectin, ccr7 and interleukin 7 receptor. Nature Immunology, 10(2), 176–184.
- Kim, G. Y., Hong, C., & Park, J.-H. (2011). Seeing is believing: Illuminating the source of in vivo interleukin-7. Immune Network, 11(1), 1–10.
- Kim, K., Lee, C.-k., Sayers, T. J., Muegge, K., & Durum, S. K. (1998). The trophic action of il-7 on pro-t cells: Inhibition of apoptosis of pro-t1,-t2, and-t3 cells correlates with bcl-2 and bax levels and is independent of fas and p53 pathways. The Journal of Immunology, 160(12), 5735–5741.
- Kim, M. S., Chung, N. G., Kim, M. S., Yoo, N. J., & Lee, S. H. (2013). Somatic mutation of il7r exon 6 in acute leukemias and solid cancers. Human Pathology, 44(4), 551–555.
- Kimura, M. Y., Pobezinsky, L. A., Guinter, T. I., Thomas, J., Adams, A., Park, J.-H., … Singer, A. (2013). Il-7 signaling must be intermittent, not continuous, during cd8+ t cell homeostasis to promote cell survival instead of cell death. Nature Immunology, 14(2), 143–151.
- Lee, H.-C., Shibata, H., Ogawa, S., Maki, K., & Ikuta, K. (2005). Transcriptional regulation of the mouse il-7 receptor α promoter by glucocorticoid receptor. The Journal of Immunology, 174(12), 7800–7806.
- Ligons, D. L., Tuncer, C., Linowes, B. A., Akcay, I. M., Kurtulus, S., Deniz, E., … Park, J.-H. (2012). Cd8 lineage-specific regulation of interleukin-7 receptor expression by the transcriptional repressor gfi1. Journal of Biological Chemistry, 287(41), 34386–34399.
- Liu, W., Putnam, A. L., Xu-Yu, Z., Szot, G. L., Lee, M. R., Zhu, S., … Bluestone, J. A. (2006). Cd127 expression inversely correlates with foxp3 and suppressive function of human cd4+ t reg cells. Journal of Experimental Medicine, 203(7), 1701–1711.
- Luckey, M. A., Kimura, M. Y., Waickman, A. T., Feigenbaum, L., Singer, A., & Park, J.-H. (2014). The transcription factor thpok suppresses runx3 and imposes cd4+ lineage fate by inducing the socs suppressors of cytokine signaling. Nature immunology, 15(7), 638–645.
- Marino, J. H., Tan, C., Taylor, A. A., Bentley, C., Van De Wiele, C. J., Ranne, R., … Teague, T. K. (2010). Differential il-7 responses in developing human thymocytes. Human immunology, 71(4), 329–333.
- Martin, C. E., Spasova, D. S., Frimpong-Boateng, K., Kim, H.-O., Lee, M., Kim, K. S., & Surh, C. D. (2017). Interleukin-7 availability is maintained by a hematopoietic cytokine sink comprising innate lymphoid cells and t cells. Immunity, 47(1), 171–182.
- Mazzucchelli, R., & Durum, S. K. (2007). Interleukin-7 receptor expression: Intelligent design. Nature Reviews Immunology, 7(2), 144–154.
- Mazzucchelli, R. I., Riva, A., & Durum, S. K. (2012). The human il-7 receptor gene: Deletions, polymorphisms and mutations. Seminars in Immunology, 24, 225–230.
- McCaughtry, T. M., Etzensperger, R., Alag, A., Tai, X., Kurtulus, S., Park, J.-H., … Singer, A. (2012). Conditional deletion of cytokine receptor chains reveals that il-7 and il-15 specify cd8 cytotoxic lineage fate in the thymus. Journal of Experimental Medicine, 209(12), 2263–2276.
- McElroy, C. A., Holland, P. J., Zhao, P., Lim, J.-M., Wells, L., Eisenstein, E., & Walsh, S. T. R. (2012). Structural reorganization of the interleukin-7 signaling complex. Proceedings of the National Academy of Sciences of the United States of America, 109(7), 2503–2508.
- Moraga, I., Spangler, J. B., Mendoza, J. L., Gakovic, M., Wehrman, T. S., Krutzik, P., & Christopher Garcia, K. (2017). Synthekines are surrogate cytokine and growth factor agonists that compel signaling through non-natural receptor dimers. eLife, 6, e22882.
- Munitic, I., Williams, J. A., Yang, Y., Dong, B., Lucas, P. J., El Kassar, N., … Ashwell, J. D. (2004). Dynamic regulation of il-7 receptor expression is required for normal thymopoiesis. Blood, 104(13), 4165–4172.
- Noguchi, M., Nakamura, Y., Russell, S. M., Ziegler, S. F., Tsang, M., Cao, X., & Leonard, W. J. (1993). Interleukin-2 receptor g chain: A functional component of the interleukin-4 receptor. Science, 262, 1877–1880.
- Noguchi, M., Sarin, A., Javad Aman, M., Nakajima, H., Shores, E. W., Henkart, P. A., & Leonard, W. J. (1997). Functional cleavage of the common cytokine receptor γ chain (γc) by calpain. Proceedings of the National Academy of Sciences of the United States of America, 94(21), 11534–11539.
- Opferman, J. T., Letai, A., Beard, C., Sorcinelli, M. D., Ong, C. C., & Korsmeyer, S. J. (2003). Development and maintenance of b and t lymphocytes requires antiapoptotic mcl-1. Nature, 426(6967), 671–676.
- Palmer, M. J., Mahajan, V. S., Chen, J., Irvine, D. J., & Lauffenburger, D. A. (2011). Signaling thresholds govern heterogeneity in il-7-receptor-mediated responses of naive cd8+ t cells. Immunology and Cell Biology, 89(5), 581–594.
- Palmer, M. J., Mahajan, V. S., Trajman, L. C., Irvine, D. J., Lauffenburger, D. A., & Chen, J. (2008). Interleukin-7 receptor signaling network: An integrated systems perspective. Cellular & Molecular Immunology, 5(2), 79–89.
- Park, J.-Y., Jo, Y., Ko, E., Luckey, M. A., Park, Y. K., Park, S.-H., … Hong, C. (2016). Soluble γc cytokine receptor suppresses il-15 signaling and impairs inkt cell development in the thymus. Scientific Reports, 6, 36962.
- Park, J.-H., Adoro, S., Guinter, T., Erman, B., Alag, A. S., Catalfamo, M., … Singer, A. (2010). Signaling by intrathymic cytokines, not t cell antigen receptors, specifies cd8 lineage choice and promotes the differentiation of cytotoxic-lineage t cells. Nature Immunology, 11(3), 257–264.
- Park, J.-H., Qing, Y., Erman, B., Appelbaum, J. S., Montoya-Durango, D., Leighton Grimes, H., & Singer, A. (2004). Suppression of il7rα transcription by il-7 and other prosurvival cytokines: A novel mechanism for maximizing il-7-dependent t cell survival. Immunity, 21(2), 289–302.
- Peschon, J. J., Morrissey, P. J., Grabstein, K. H., Ramsdell, F. J., Maraskovsky, E., Gliniak, B. C., … Davison, B. L. (1994). Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. Journal of Experimental Medicine, 180(5), 1955–1960.
- Raeber, M. E., Zurbuchen, Y., Impellizzieri, D., & Boyman, O. (2018). The role of cytokines in t-cell memory in health and disease. Immunological Reviews, 283(1), 176–193.
- Rathmell, J. C., Farkash, E. A., Gao, W., & Thompson, C. B. (2001). Il-7 enhances the survival and maintains the size of naive t cells. The Journal of Immunology, 167(12), 6869–6876.
- Reynolds, J., Coles, M., Lythe, G., & Molina-París, C. (2013). Mathematical model of naive t cell division and survival il-7 thresholds. Frontiers in Immunology, 4, 434.
- Ribeiro, D., Melão, A., & Barata, J. T. (2013). Il-7r-mediated signaling in t-cell acute lymphoblastic leukemia. Advances in Biological Regulation, 53(2), 211–222.
- Rochman, Y., Spolski, R., & Leonard, W. J. (2009). New insights into the regulation of t cells by γc family cytokines. Nature Reviews Immunology, 9(7), 480–490.
- Rose, T., Pillet, A.-H., Lavergne, V., Tamarit, B., Lenormand, P., Rousselle, J.-C., … Thèze, J. (2010). Interleukin-7 compartmentalizes its receptor signaling complex to initiate cd4 t lymphocyte response. Journal of Biological Chemistry, 285(20), 14898–14908.
- Schluns, K. S., Kieper, W. C., Jameson, S. C., & Lefrançois, L. (2000). Interleukin-7 mediates the homeostasis of naive and memory cd8 t cells in vivo. Nature Immunology, 1(5), 426–432.
- Sekar, J. A. P., & Faeder, J. R. (2017). An introduction to rule-based modeling of immune receptor signaling. arXiv preprint arXiv, 1709, 06658.
- Shimizu, A., Kondo, S., Sabe, H., Ishida, N., & Honjo, T. (1986). Structure and function of the interleukin 2 receptor: Affinity conversion model. Immunological Reviews, 92(1), 103–120.
- Shochat, C., Tal, N., Gryshkova, V., Birger, Y., Bandapalli, O. R., Cazzaniga, G., … Izraeli, S. (2014). Novel activating mutations lacking cysteine in type i cytokine receptors in acute lymphoblastic leukemia. Blood, 124(1), 106–110.
- Singer, A., Adoro, S., & Park, J.-H. (2008). Lineage fate and intense debate: Myths, models and mechanisms of cd4-versus cd8-lineage choice. Nature Reviews Immunology, 8(10), 788–801.
- Takada, K., & Jameson, S. C. (2009). Naive t cell homeostasis: From awareness of space to a sense of place. Nature Reviews Immunology, 9(12), 823–832.
- Tal, N., Shochat, C., Geron, I., Bercovich, D., & Izraeli, S. (2014). Interleukin 7 and thymic stromal lymphopoietin: From immunity to leukemia. Cellular and Molecular Life Sciences, 71(3), 365–378.
- Tan, J. T., Dudl, E., LeRoy, E., Murray, R., Sprent, J., Weinberg, K. I., & Surh, C. D. (2001). Il-7 is critical for homeostatic proliferation and survival of naive t cells. Proceedings of the National Academy of Sciences of the United States of America, 98(15), 8732–8737.
- Venkitaraman, A. R., & Cowling, R. J. (1994). Interleukin-7 induces the association of phosphatidylinositol 3-kinase with the α chain of the interleukin-7 receptor. European Journal of Immunology, 24(9), 2168–2174.
- von Freeden-Jeffry, U., Vieira, P., Lucian, L. A., McNeil, T., Burdach, S. E., & Murray, R. (1995). Lymphopenia in interleukin (il)-7 gene-deleted mice identifies il-7 as a nonredundant cytokine. Journal of Experimental Medicine, 181(4), 1519–1526.
- Waickman, A. T., Park, J.-Y., & Park, J.-H. (2016). The common γ-chain cytokine receptor: Tricks-and-treats for t cells. Cellular and Molecular Life Sciences, 73(2), 253–269.
- Waldmann, T. A. (2015). The shared and contrasting roles of il2 and il15 in the life and death of normal and neoplastic lymphocytes: Implications for cancer therapy. Cancer Immunology Research, 3(3), 219–227.
- Walsh, S. T. R. (2012). Structural insights into the common γ-chain family of cytokines and receptors from the interleukin-7 pathway. Immunological Reviews, 250(1), 303–316.
- Watanabe, M., Ueno, Y., Yajima, T., Okamoto, S., Hayashi, T., Yamazaki, M., … Hibi, T. (1998). Interleukin 7 transgenic mice develop chronic colitis with decreased interleukin 7 protein accumulation in the colonic mucosa. Journal of Experimental Medicine, 187(3), 389–402.
- Wofford, J. A., Wieman, H. L., Jacobs, S. R., Zhao, Y., & Rathmell, J. C. (2008). Il-7 promotes glut1 trafficking and glucose uptake via stat5-mediated activation of akt to support t-cell survival. Blood, 111(4), 2101–2111.
- Xue, H.-H., Bollenbacher, J., Rovella, V., Tripuraneni, R., Du, Y.-B., Liu, C.-Y., … Leonard, W. J. (2004). Ga binding protein regulates interleukin 7 receptor α-chain gene expression in t cells. Nature Immunology, 5(10), 1036–1044.
- Yu, Q., Erman, B., Bhandoola, A., Sharrow, S. O., & Singer, A. (2003). In vitro evidence that cytokine receptor signals are required for differentiation of double positive thymocytes into functionally mature cd8+ t cells. Journal of Experimental Medicine, 197(4), 475–487.
- Yu, Q., Erman, B., Park, J.-H., Feigenbaum, L., & Singer, A. (2004). Il-7 receptor signals inhibit expression of transcription factors tcf-1, lef-1, and rorγt. Journal of Experimental Medicine, 200(6), 797–803.
- Yu, Q., Park, J.-H., Doan, L. L., Erman, B., Feigenbaum, L., & Singer, A. (2006). Cytokine signal transduction is suppressed in preselection double-positive thymocytes and restored by positive selection. Journal of Experimental Medicine, 203(1), 165–175.
- Zenatti, P. P., Ribeiro, D., Li, W., Zuurbier, L., Silva, M. C., Paganin, M., … Barata, J. T. (2011). Oncogenic il7r gain-of-function mutations in childhood t-cell acute lymphoblastic leukemia. Nature Genetics, 43(10), 932–939.
