The role of the T-helper/T-suppressor ratio in the adaptive immune response: a dynamical model. (English) Zbl 1411.92129
Summary: Recent experimental studies have suggested the ratio between T-helper and T-suppressor lymphocytes as an index of immunosuppression in HIV, cancer, immunosenescence and inflammatory and auto-immune diseases. However, a quantitative understanding of the impact of this ratio on the immune response has lagged behind data and its validity as a tool for prognostic monitoring or therapeutic target remains an open question. In this work, we use statistical physics and dynamical systems approaches to analyze the time-dependent response to an antigen, of a simplified model of the adaptive immune system, which comprises B, T-helper and T-suppressor lymphocytes. The model is remarkably robust against changes in the noise level and kinetic parameters, but it is very sensitive to changes in the ratio between T-helper and T-suppressor lymphocytes, exhibiting, in particular, a transition from a responsive to an immuno-suppressed phase, as the ratio is lowered below a critical value, which is in line with experiments. This result supports the validity of the T-helper/T-suppressor ratio as an index of immunosuppression and may provide a useful theoretical benchmark to interpret and compare experiments.
Keywords:
T-helper/T-suppressor; cd4/cd8; immune response; clonal expansion; immune networks; th/treg; lymphocyte homeostasisReferences:
| [1] | Nowak, M. A.; May, R. M., Virus Dynamics: Mathematical Principles of Immunology and Virology, (2000), New York: Oxford University Press, New York · Zbl 1101.92028 |
| [2] | León, K.; Lage, A.; Carneiro, J., J. Theor. Biol., 225, 107-126, (2003) · Zbl 1464.92057 · doi:10.1016/S0022-5193(03)00226-1 |
| [3] | Burroughs, N. J.; de Oliveira, B. M P. M.; Pinto, A. A., J. Theor. Biol., 241, 13-141, (2006) · Zbl 1447.92086 · doi:10.1016/j.jtbi.2005.11.010 |
| [4] | Fouchet, D.; Regoes, R., PLoS One, 3, e2306, (2008) · doi:10.1371/journal.pone.0002306 |
| [5] | Alexander, H. K.; Wahl, L. M., Bull. Math. Biol., 73, 33-71, (2011) · Zbl 1209.92026 · doi:10.1007/s11538-010-9519-2 |
| [6] | Gadhamsetty, S.; Mare, A. F M.; Beltman, J. B.; de Boer, R. J., Biophys. J., 112, 1221-1235, (2017) · doi:10.1016/j.bpj.2017.02.008 |
| [7] | Kim, P. S.; Lee, P. P.; Levy, D., J. Theor. Biol., 246, 33-69, (2007) · Zbl 1451.92097 · doi:10.1016/j.jtbi.2006.12.012 |
| [8] | Carneiro, J., Immunol. Rev., 216, 48-68, (2007) · doi:10.1111/j.1600-065X.2007.00487.x |
| [9] | Antia, R.; Bergstrom, C. T.; Pilyugin, S. S.; Kaech, S. M.; Ahmed, R., J. Theor. Biol., 221, 585-598, (2003) · Zbl 1464.92037 · doi:10.1006/jtbi.2003.3208 |
| [10] | Onsum, M.; Rao, C. V., PLoS Comput. Biol., 3, e36, (2007) · doi:10.1371/journal.pcbi.0030036 |
| [11] | Carneiro, J., J. Comput. Appl. Math., 184, 77-100, (2005) · Zbl 1072.92021 · doi:10.1016/j.cam.2004.10.025 |
| [12] | Bogle, G.; Dunbar, P. R., Immunol. Cell Biol., 88, 172-179, (2009) · doi:10.1038/icb.2009.78 |
| [13] | Chiacchio, F., Biomed. Res. Int., 2014, (2014) · doi:10.1155/2014/907171 |
| [14] | Scherer, A.; Salathe, M.; Bonhoeffer, S., PLoS Comput. Biol., 2, e109, (2006) · doi:10.1371/journal.pcbi.0020109 |
| [15] | Casal, A., J. Theor. Biol., 236, 376-391, (2005) · Zbl 1442.92028 · doi:10.1016/j.jtbi.2005.03.019 |
| [16] | Mora, T.; Walczak, A. M.; Bialek, W.; Callan, C. G., Proc. Natl Acad. Sci., 107, 5405-5410, (2010) · doi:10.1073/pnas.1001705107 |
| [17] | Asti, L.; Uguzzoni, G.; Marcatili, P.; Pagnani, A., PLoS Comput. Biol., 12, e1004870, (2016) · doi:10.1371/journal.pcbi.1004870 |
| [18] | Greene, J.; Birtwistle, M. R.; Ignatowicz, L.; Rempala, G. A., J. Theor. Biol., 326, 1-10, (2013) · Zbl 1322.92014 · doi:10.1016/j.jtbi.2013.02.009 |
| [19] | Boelen, L., PLoS Comput. Biol., 12, e1004796, (2016) · doi:10.1371/journal.pcbi.1004796 |
| [20] | Parisi, G., Proc. Natl Acad. Sci. USA, 87, 429-433, (1990) · doi:10.1073/pnas.87.1.429 |
| [21] | Barra, A.; Agliari, E., J. Stat. Mech., (2010) · doi:10.1088/1742-5468/2010/07/P07004 |
| [22] | Agliari, E.; Barra, A.; Guerra, F.; Moauro, F., J. Theor. Biol., 287, 48-63, (2011) · Zbl 1397.92123 · doi:10.1016/j.jtbi.2011.07.027 |
| [23] | Agliari, E.; Annibale, A.; Barra, A.; Coolen, A. C C.; Tantari, D., J. Phys. A: Math. Theor., 46, (2013) · Zbl 1300.92040 · doi:10.1088/1751-8113/46/41/415003 |
| [24] | Agliari, E.; Annibale, A.; Barra, A.; Coolen, A. C C.; Tantari, D., J. Phys. A: Math. Theor., 46, (2013) · Zbl 1272.68339 · doi:10.1088/1751-8113/46/33/335101 |
| [25] | Bartolucci, S.; Mozeika, A.; Annibale, A., J. Stat. Mech., 2016, (2016) · Zbl 1456.92040 · doi:10.1088/1742-5468/2016/08/083402 |
| [26] | Barra, A.; Agliari, E., Physica A, 389, 5903-5911, (2010) · doi:10.1016/j.physa.2010.09.004 |
| [27] | Bartolucci, S.; Annibale, A., J. Stat. Mech., (2015) · Zbl 1456.92078 · doi:10.1088/1742-5468/2015/08/P08017 |
| [28] | Maeda, N.; Sekigawa, I.; Iida, N.; Matsumoto, M.; Hashimoto, H.; Hirose, S., Scand. J. Rheumatol., 28, 166-170, (1999) · doi:10.1080/03009749950154248 |
| [29] | Beckham, J. C., J. Clin. Immunol., 12, 353-361, (1992) · doi:10.1007/BF00920793 |
| [30] | Carvajal Alegria, G.; Gazeau, P.; Hillion, S.; Daïen, C. I.; Cornec, D. Y K., Clin. Rev. Allergy Immunol., 53, 219-236, (2017) · doi:10.1007/s12016-017-8608-5 |
| [31] | Al-Sakkaf, L.; Pozzilli, P.; Tarn, A. C.; Schwarz, G.; Gale, E. A.; Bottazzo, G. F., Diabetologia, 32, 322-325, (1989) · doi:10.1007/BF00265550 |
| [32] | Tancini, G.; Barni, S.; Rescaldani, E.; Fiorelli, G.; Vivani, S.; Lissoni, P., Oncology, 47, 381-384, (1990) · doi:10.1159/000226852 |
| [33] | Shah, W.; Yan, X.; Jing, L.; Zhou, Y.; Chen, H.; Wang, Y., Cell. Mol. Immunol., 8, 59-66, (2011) · doi:10.1038/cmi.2010.56 |
| [34] | Wikby, A.; Mansson, I. A.; Johansson, B.; Strindhall, J.; Nilsson, S. E., Biogerontology, 9, 299-308, (2008) · doi:10.1007/s10522-008-9138-6 |
| [35] | Kamen-Siegel, L.; Rodin, J.; Seligman, M. E.; Dwyer, J. J., Health Psychol., 10, 229-235, (1991) · doi:10.1037/0278-6133.10.4.229 |
| [36] | Strindhall, J., Age, 35, 985-991, (2013) · doi:10.1007/s11357-012-9400-3 |
| [37] | Appay, V.; Sauce, D., J. Pathol., 214, 231-241, (2008) · doi:10.1002/path.2276 |
| [38] | Serrano-Villar, S., HIV Med., 15, 40-49, (2014) · doi:10.1111/hiv.12081 |
| [39] | Serrano-Villar, S., PLoS Pathog., 10, e1004078, (2014) · doi:10.1371/journal.ppat.1004078 |
| [40] | Serrano-Villar, S.; Deeks, S. G., Lancet HIV, 2, e76-e77, (2015) · doi:10.1016/S2352-3018(15)00018-1 |
| [41] | Trickey, A., Clin. Infect. Dis., 65, 959-966, (2017) · doi:10.1093/cid/cix466 |
| [42] | Hocqueloux, L., J. Antimicrob. Chemother., 68, 1169-1178, (2013) · doi:10.1093/jac/dks533 |
| [43] | Jain, V., J. Infect. Dis., 208, 1202-1211, (2013) · doi:10.1093/infdis/jit311 |
| [44] | Chun, T. W., J. Infect. Dis., 185, 1672-1676, (2002) · doi:10.1086/340521 |
| [45] | Lu, W.; Mehraj, V.; Vyboh, K.; Cao, W.; Li, T.; Routy, J. P., J. Int. AIDS Soc., 18, 20052, (2015) · doi:10.7448/IAS.18.1.20052 |
| [46] | McBride, J. A.; Striker, R., PLoS Pathog., 13, e1006624, (2017) · doi:10.1371/journal.ppat.1006624 |
| [47] | Hall, B. M.; Pearce, N. W.; Gurley, K. E.; Dorsch, S. E., J. Exp. Med., 171, 141-157, (1990) · doi:10.1084/jem.171.1.141 |
| [48] | Sakaguchi, S.; Sakaguchi, N.; Asano, M.; Itoh, M.; Toda, M., J. Immunol., 155, 1151-1164, (1995) |
| [49] | Sakaguchi, S.; Wing, K.; Onishi, Y.; Prieto-Martin, P.; Yamaguchi, T., Int. Immunol., 21, 1105-1111, (2009) · doi:10.1093/intimm/dxp095 |
| [50] | Magg, T.; Mannert, J.; Ellwart, J. W.; Schmid, I.; Albert, M. H., Eur. J. Immunol., 42, 1627-1638, (2012) · doi:10.1002/eji.201141838 |
| [51] | Brivio, F., In Vivo, 22, 647-650, (2008) |
| [52] | Chang, C.; Wu, S. Y.; Kang, Y. W.; Lin, K. P.; Chen, T. Y.; Medeiros, L. J.; Chang, K. C., Am. J. Clin. Pathol., 144, 935-944, (2015) · doi:10.1309/AJCPUJGMVV6ZF4GG |
| [53] | Valverde-Villegas, J. M.; Cotta Matte, M. C.; de Medeiros, R. M.; Bogo Chies, J. A., J. Immunol. Res., 2015, (2015) · doi:10.1155/2015/647916 |
| [54] | Miles, B., Nat. Commun., 6, 8608, (2015) · doi:10.1038/ncomms9608 |
| [55] | Li, D., Clin. Exp. Immunol., 165, 363-371, (2011) · doi:10.1111/j.1365-2249.2011.04435.x |
| [56] | Jagger, A.; Shimojima, Y.; Goronzy, J. J.; Weyand, C. M., Gerontology, 60, 130-137, (2014) · doi:10.1159/000355303 |
| [57] | Yu, Z. X.; Ji, M. S.; Yan, J.; Cai, Y.; Liu, J.; Yang, H. F.; Li, Y.; Jin, Z. C.; Zheng, J. X., Crit. Care, 19, 82, (2015) · doi:10.1186/s13054-015-0811-2 |
| [58] | Preston, C. C., PLoS One, 8, (2013) · doi:10.1371/journal.pone.0080063 |
| [59] | Boyce, C.; Lane, C.; Hingorani, R.; McIntyre, C.; Ruitenberg, J.; Ghanekar, S., BD Biosci. Appl. Note, (2010) |
| [60] | Abbas, A. K.; Lichtman, A. H.; Pillai, S., Basic Immunology: Functions, Disorders of the Immune System, (2009), Philadelphia, PA: Saunders, Philadelphia, PA |
| [61] | MacLennan, I. C., Annu. Rev. Immunol., 12, 117-139, (1994) · doi:10.1146/annurev.iy.12.040194.001001 |
| [62] | De Silva, N. S.; Klein, U., Nat. Rev. Immunol., 15, 137-148, (2015) · doi:10.1038/nri3804 |
| [63] | Corthay, A., Scand. J. Immunol., 70, 326-336, (2009) · doi:10.1111/j.1365-3083.2009.02308.x |
| [64] | Hall, B. M.; Tran, G. T.; Verma, N. D.; Plain, K. M.; Hodgkinson, C. M.; Hodgkinson, S. J., Frontiers Immunol., 4, 208, (2013) · doi:10.3389/fimmu.2013.00208 |
| [65] | Zhao, D. M.; Thornton, A. M.; Di Paolo, R. J.; Shevach, E. M., Blood, 107, 3925-3932, (2006) · doi:10.1182/blood-2005-11-4502 |
| [66] | Vignali, D. A.; Collison, L. W.; Workman, C. J., Nat. Rev. Immunol., 8, 523-532, (2008) · doi:10.1038/nri2343 |
| [67] | Wang, P.; Zheng, S. G., Int. J. Clin. Exp. Pathol., 6, 2668-2674, (2013) |
| [68] | Gotot, J., Proc. Natl Acad. Sci., 109, 10468-10473, (2012) · doi:10.1073/pnas.1201131109 |
| [69] | Lim, H. W.; Hillsamer, P.; Banham, A. H.; Kim, C. H., J. Immunol., 175, 4180-4183, (2005) · doi:10.4049/jimmunol.175.7.4180 |
| [70] | Iikuni, N.; Loureno, E. V.; Hahn, B. H.; La Cava, A., J. Immunol., 183, 1518-1522, (2009) · doi:10.4049/jimmunol.0901163 |
| [71] | Lankar, D.; Vincent-Schneider, H.; Briken, V.; Yokozeki, T.; Raposo, G.; Bonnerot, C., J. Exp. Med., 195, 461-472, (2002) · doi:10.1084/jem.20011543 |
| [72] | Guzman-Rojas, L.; Sims-Mourtada, J. C.; Rangel, R.; Martinez-Valdez, H., Immunology, 107, 167-175, (2002) · doi:10.1046/j.1365-2567.2002.01494.x |
| [73] | Jenkins, M. K.; Chu, H. H.; McLachlan, J. B.; Moon, J. J., Ann. Rev. Immunol., 28, 275-294, (2010) · doi:10.1146/annurev-immunol-030409-101253 |
| [74] | Glanville, J.; Zhai, W.; Berka, J.; Telman, D.; Huerta, G.; Mehta, G. R., Proc. Natl Acad. Sci., 106, 20216-20221, (2009) · doi:10.1073/pnas.0909775106 |
| [75] | Sigal, N. H.; Klinman, N. R.; Dixon, Fj; Kunkel, Hg, Adv. Immunol., 255-337, (1978), New York: Elsevier, New York · doi:10.1016/S0065-2776(08)60232-1 |
| [76] | Desponds, J.; Mora, T.; Walczak, A. M., Proc. Natl Acad. Sci., 113, 274-279, (2016) · doi:10.1073/pnas.1512977112 |
| [77] | Gibson, B.; Wilson, D.; Feil, E.; Eyre-Walker, A., Proc. R. Soc. B, 285, 20180789, (2018) · doi:10.1098/rspb.2018.0789 |
| [78] | Emery, V. C.; Cope, A. V.; Bowen, E. F.; Gor, D.; Griffithsa, P. D., J. Exp. Med., 190, 177-182, (1999) · doi:10.1084/jem.190.2.177 |
| [79] | Janeway, C. A.; Travers, P.; Walport, M.; Shlomchik, M. J., The immune system in health and disease, Immunobiology, (2001), New York: Garland Science, New York |
| [80] | Coolen, A. C C.; Ruijgrok, W. T., Phys. Rev. A, 38, 4253-4255, (1988) · doi:10.1103/PhysRevA.38.4253 |
| [81] | Sherrington, D.; Coolen, A. C C.; Laughton, S. N.; Hao, B-L, STATPHYS 19, p 401-409, (1996), Singapore: World Scientific, Singapore · doi:10.1142/2799 |
| [82] | Bartolucci, S.; Annibale, A., J. Phys. A: Math. Theor., 47, (2014) · Zbl 1308.82039 · doi:10.1088/1751-8113/47/41/415001 |
| [83] | Coolen, A. C C.; Kühn, R.; Sollich, P., Theory of Neural Information Processing Systems, (2005), New York: Oxford University Press, New York · Zbl 1117.68064 |
| [84] | Plas, D. R.; Rathmell, J. C.; Thompson, C. B., Nat. Immunol., 3, 515-521, (2002) · doi:10.1038/ni0602-515 |
| [85] | Kepler, T. B., Frontiers Immunol., 5, 170, (2014) · doi:10.3389/fimmu.2014.00170 |
| [86] | Meyer-Hermann, M. E.; Maini, P. K.; Iber, D., Math. Med. Biol., 23, 255-277, (2006) · Zbl 1098.92041 · doi:10.1093/imammb/dql012 |
| [87] | Kepler, T. B.; Perelson, A. S., Immunol. Today, 14, 412-415, (1993) · doi:10.1016/0167-5699(93)90145-B |
| [88] | Amitai, A.; Mesin, L.; Victora, G. D.; Kardar, M.; Chakraborty, A. K., Frontiers Microbiol., 8, 1693, (2017) · doi:10.3389/fmicb.2017.01693 |
| [89] | Reverberi, R.; Reverberi, L., Blood Transfus., 5, 93-101, (2007) · doi:10.2450/2007.0018-07 |
| [90] | Tsourkas, P. K.; Liu, W.; Das, S. C.; Pierce, S. K.; Raychaudhuri, S., Cell. Mol. Immunol., 9, 62-74, (2012) · doi:10.1038/cmi.2011.29 |
| [91] | Anderson, S. M., J. Immunol., 183, 7314-7325, (2009) · doi:10.4049/jimmunol.0902452 |
| [92] | Chaput, N., J. Immunol., 179, 4969-4978, (2007) · doi:10.4049/jimmunol.179.8.4969 |
| [93] | Mozeika, A.; Coolen, A. C C., J. Phys. A: Math. Theor., 50, (2017) · Zbl 1357.92033 · doi:10.1088/1751-8121/50/3/035602 |
| [94] | Lythe, G.; Callard, R. E.; Hoare, R. L.; Molina-París, C., J. Theor. Biol., 389, 214-224, (2016) · Zbl 1343.92095 · doi:10.1016/j.jtbi.2015.10.016 |
| [95] | Gillespie, D. T., J. Phys. Chem., 81, 2340-2361, (1977) · doi:10.1021/j100540a008 |
| [96] | Gibson, K. L., Aging Cell, 8, 18-25, (2009) · doi:10.1111/j.1474-9726.2008.00443.x |
This reference list is based on information provided by the publisher or from digital mathematics libraries. Its items are heuristically matched to zbMATH identifiers and may contain data conversion errors. In some cases that data have been complemented/enhanced by data from zbMATH Open. This attempts to reflect the references listed in the original paper as accurately as possible without claiming completeness or a perfect matching.
