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Published in: European Journal of Applied Physiology 8/2017

Open Access 01-08-2017 | Original Article

T-regulatory cells exhibit a biphasic response to prolonged endurance exercise in humans

Authors: Tom Clifford, Matthew J. Wood, Philip Stocks, Glyn Howatson, Emma J. Stevenson, Catharien M. U. Hilkens

Published in: European Journal of Applied Physiology | Issue 8/2017

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Abstract

Purpose

T-regulatory cells (Tregs) are a sub-population of lymphocytes that act to suppress aberrant immune responses. We investigated changes in the numbers of naïve and terminally differentiated Tregs in the peripheral blood to establish their role in the immuno-suppressive response to prolonged exercise.

Methods

Blood was drawn from seventeen experienced runners (age 40 ± 12 years; height 1.75 ± 0.08 m; mass 71.4 ± 10.8 kg) before, ~1 h after (POST-1h), and on the day following the marathon (POST-1d). Tregs (CD3+CD4+Foxp3+CD25++CD127) were analysed in peripheral blood mononuclear cells using flow cytometry. The markers CD45RA and HLA-DR were included to define naïve and terminally differentiated Tregs, respectively.

Results

The absolute number of Tregs decreased (27%) POST-1h marathon (P < 0.001) but increased (21%) at POST-1d (P < 0.01). Naïve CD45RA+ Tregs fell by 39% POST-1h (P < 0.01) but were unaffected POST-1d (P > 0.05). In contrast, an increased number of Tregs expressing HLA-DR was observed at POST-1d (P < 0.01). Interleukin (IL)-1β, IL-6, IL-8 and IL-10 levels in the serum all increased POST-1h (P > 0.05) but returned to pre-exercise levels POST-1d. The suppressive cytokine, transforming growth factor-beta, was unaffected by the marathon (P > 0.05).

Conclusions

These results suggest that Tregs do not play a major role in immune suppression in the early hours of recovery from a marathon. However, terminally differentiated HLA-DR+ Tregs are mobilized the following day, which could represent a compensatory attempt by the host to restore immune homeostasis and limit excessive cell damage.
Literature
go back to reference Baecher-Allan C, Wolf E, Hafler DA (2006) MHC class II expression identifies functionally distinct human regulatory T cells. J Immunol 176:4622–4631CrossRefPubMed Baecher-Allan C, Wolf E, Hafler DA (2006) MHC class II expression identifies functionally distinct human regulatory T cells. J Immunol 176:4622–4631CrossRefPubMed
go back to reference Clifford T, Allerton DM, Brown MA, Harper L, Horsburgh S, Keane KM, Stevenson EJ, Howatson G (2016) Minimal muscle damage after a marathon and no influence of beetroot juice on inflammation and recovery. Appl Physiol Nutr Metab. doi:10.1139/apnm-2016-0525 PubMed Clifford T, Allerton DM, Brown MA, Harper L, Horsburgh S, Keane KM, Stevenson EJ, Howatson G (2016) Minimal muscle damage after a marathon and no influence of beetroot juice on inflammation and recovery. Appl Physiol Nutr Metab. doi:10.​1139/​apnm-2016-0525 PubMed
go back to reference Dill DB, Costill DL (1974) Calculation of percentage changes in volumes of blood, plasma, and red cells in dehydration. J Appl Physiol 37:247–248PubMed Dill DB, Costill DL (1974) Calculation of percentage changes in volumes of blood, plasma, and red cells in dehydration. J Appl Physiol 37:247–248PubMed
go back to reference Fountoulakis S, Vartholomatos G, Kolaitis N, Frillingos S, Philippou G, Tsatsoulis A (2008) HLA-DR expressing peripheral T regulatory cells in newly diagnosed patients with different forms of autoimmune thyroid disease. Thyroid 18:1195–1200. doi:10.1089/thy.2008.0089 CrossRefPubMed Fountoulakis S, Vartholomatos G, Kolaitis N, Frillingos S, Philippou G, Tsatsoulis A (2008) HLA-DR expressing peripheral T regulatory cells in newly diagnosed patients with different forms of autoimmune thyroid disease. Thyroid 18:1195–1200. doi:10.​1089/​thy.​2008.​0089 CrossRefPubMed
go back to reference Gleeson M, Bishop NC (2005) The T cell and NK cell immune response to exercise. Ann Transplant 10:43–48PubMed Gleeson M, Bishop NC (2005) The T cell and NK cell immune response to exercise. Ann Transplant 10:43–48PubMed
go back to reference Gleeson M, Pyne DB (2015) Respiratory inflammation and infections in high-performance athletes. Immunol Cell Biol 94:124–131CrossRefPubMed Gleeson M, Pyne DB (2015) Respiratory inflammation and infections in high-performance athletes. Immunol Cell Biol 94:124–131CrossRefPubMed
go back to reference Handzlik MK, Shaw AJ, Dungey M, Bishop NC, Gleeson M (2013) The influence of exercise training status on antigen-stimulated IL-10 production in whole blood culture and numbers of circulating regulatory T cells. Eur J Appl Physiol 113:1839–1848. doi:10.1007/s00421-013-2614-y CrossRefPubMed Handzlik MK, Shaw AJ, Dungey M, Bishop NC, Gleeson M (2013) The influence of exercise training status on antigen-stimulated IL-10 production in whole blood culture and numbers of circulating regulatory T cells. Eur J Appl Physiol 113:1839–1848. doi:10.​1007/​s00421-013-2614-y CrossRefPubMed
go back to reference Hikida RS, Staron RS, Hagerman FC, Sherman WM, Costill DL (1983) Muscle fiber necrosis associated with human marathon runners. J Neurol Sci 59:185–203CrossRefPubMed Hikida RS, Staron RS, Hagerman FC, Sherman WM, Costill DL (1983) Muscle fiber necrosis associated with human marathon runners. J Neurol Sci 59:185–203CrossRefPubMed
go back to reference Krüger K, Alack K, Ringseis R, Mink L, Pfeifer E, Schinle M, Gindler K, Kimmelmann L, Walscheid R, Muders K, Frech T (2016) Apoptosis of T-cell subsets after acute high-intensity interval exercise. Med Sci Sports Exerc 48:2021–2029. doi:10.1249/MSS.0000000000000979 CrossRefPubMed Krüger K, Alack K, Ringseis R, Mink L, Pfeifer E, Schinle M, Gindler K, Kimmelmann L, Walscheid R, Muders K, Frech T (2016) Apoptosis of T-cell subsets after acute high-intensity interval exercise. Med Sci Sports Exerc 48:2021–2029. doi:10.​1249/​MSS.​0000000000000979​ CrossRefPubMed
go back to reference Nieman DC (1997) Immune response to heavy exertion. J Appl Physiol 82:1385–1394PubMed Nieman DC (1997) Immune response to heavy exertion. J Appl Physiol 82:1385–1394PubMed
go back to reference Nieman DC, Henson DA, Butterworth DE, Warren BJ, Davis JM, Fagoaga OR, Nehlsen-Cannarella SL (1997) Vitamin C supplementation does not alter the immune response to 2.5 hours of running. Int J Sport Nutr 7:173–184CrossRefPubMed Nieman DC, Henson DA, Butterworth DE, Warren BJ, Davis JM, Fagoaga OR, Nehlsen-Cannarella SL (1997) Vitamin C supplementation does not alter the immune response to 2.5 hours of running. Int J Sport Nutr 7:173–184CrossRefPubMed
go back to reference Nieman DC, Henson DA, Smith LL, Utter AC, Vinci DM, Davis JM, Kaminsky DE, Shute M (2001) Cytokine changes after a marathon race. J Appl Physiol 91:109–114PubMed Nieman DC, Henson DA, Smith LL, Utter AC, Vinci DM, Davis JM, Kaminsky DE, Shute M (2001) Cytokine changes after a marathon race. J Appl Physiol 91:109–114PubMed
go back to reference Rehm KE, Elci OU, Hahn K, Marshall GD Jr (2013) The impact of self-reported psychological stress levels on changes to peripheral blood immune biomarkers in recreational marathon runners during training and recovery. NeuroImmunoModulation 20:164–176. doi:10.1159/000346795 CrossRefPubMed Rehm KE, Elci OU, Hahn K, Marshall GD Jr (2013) The impact of self-reported psychological stress levels on changes to peripheral blood immune biomarkers in recreational marathon runners during training and recovery. NeuroImmunoModulation 20:164–176. doi:10.​1159/​000346795 CrossRefPubMed
go back to reference Shanely RA, Nieman DC, Zwetsloot KA, Knab AM, Imagita H, Luo B, Davis B, Zubeldia JM (2014) Evaluation of Rhodiola rosea supplementation on skeletal muscle damage and inflammation in runners following a competitive marathon. Brain Behav Immun 39:204–210. doi:10.1016/j.bbi.2013.09.005 CrossRefPubMed Shanely RA, Nieman DC, Zwetsloot KA, Knab AM, Imagita H, Luo B, Davis B, Zubeldia JM (2014) Evaluation of Rhodiola rosea supplementation on skeletal muscle damage and inflammation in runners following a competitive marathon. Brain Behav Immun 39:204–210. doi:10.​1016/​j.​bbi.​2013.​09.​005 CrossRefPubMed
go back to reference Simpson RJ, Florida-James GD, Cosgrov C, Whyte GP, Macrae S, Pircher H, Guy K (2007) High-intensity exercise elicits the mobilization of senescent T lymphocytes into the peripheral blood compartment in human subjects. J Appl Physiol 103:396–401. doi:10.1152/japplphysiol.00007.2007 CrossRefPubMed Simpson RJ, Florida-James GD, Cosgrov C, Whyte GP, Macrae S, Pircher H, Guy K (2007) High-intensity exercise elicits the mobilization of senescent T lymphocytes into the peripheral blood compartment in human subjects. J Appl Physiol 103:396–401. doi:10.​1152/​japplphysiol.​00007.​2007 CrossRefPubMed
go back to reference Slattery K, Bentley D, Coutts AJ (2015) The role of oxidative, inflammatory and neuroendocrinological systems during exercise stress in athletes: implications of antioxidant supplementation on physiological adaptation during intensified physical training. Sports Med 45:453–471CrossRefPubMed Slattery K, Bentley D, Coutts AJ (2015) The role of oxidative, inflammatory and neuroendocrinological systems during exercise stress in athletes: implications of antioxidant supplementation on physiological adaptation during intensified physical training. Sports Med 45:453–471CrossRefPubMed
go back to reference Suzuki K, Yamada M, Kurakake S, Okamura N, Yamaya K, Liu Q, Kudoh S, Kowatari K, Nakaji S, Sugawara K (2000) Circulating cytokines and hormones with immunosuppressive but neutrophil-priming potentials rise after endurance exercise in humans. Eur J Appl Physiol 81:281–287. doi:10.1007/s004210050044 CrossRefPubMed Suzuki K, Yamada M, Kurakake S, Okamura N, Yamaya K, Liu Q, Kudoh S, Kowatari K, Nakaji S, Sugawara K (2000) Circulating cytokines and hormones with immunosuppressive but neutrophil-priming potentials rise after endurance exercise in humans. Eur J Appl Physiol 81:281–287. doi:10.​1007/​s004210050044 CrossRefPubMed
go back to reference Toft AD, Thorn M, Ostrowski K, Asp S, Møller K, Iversen S, Hermann C, Søndergaard SR, Pedersen BK (2000) N-3 polyunsaturated fatty acids do not affect cytokine response to strenuous exercise. J Appl Physiol 89:2401–2406PubMed Toft AD, Thorn M, Ostrowski K, Asp S, Møller K, Iversen S, Hermann C, Søndergaard SR, Pedersen BK (2000) N-3 polyunsaturated fatty acids do not affect cytokine response to strenuous exercise. J Appl Physiol 89:2401–2406PubMed
go back to reference Walsh NP, Gleeson M, Shephard RJ, Gleeson M, Woods JA, Bishop N, Fleshner M, Green C, Pedersen BK, Hoffman-Goete L, Rogers CJ (2011) Position statement part one: immune function and exercise. Exerc Immunol Rev 17:6–63PubMed Walsh NP, Gleeson M, Shephard RJ, Gleeson M, Woods JA, Bishop N, Fleshner M, Green C, Pedersen BK, Hoffman-Goete L, Rogers CJ (2011) Position statement part one: immune function and exercise. Exerc Immunol Rev 17:6–63PubMed
go back to reference Weinhold M, Shimabukuro-Vornhagen A, Franke A, Theurich S, Wahl P, Hallek M, Schmidt A, Schinköthe T, Mester J, von Bergwelt-Baildon M, Bloch W (2016) Physical exercise modulates the homeostasis of human regulatory T cells. J Allergy Clin Immunol 137(1607–1610):e1608. doi:10.1016/j.jaci.2015.10.035 Weinhold M, Shimabukuro-Vornhagen A, Franke A, Theurich S, Wahl P, Hallek M, Schmidt A, Schinköthe T, Mester J, von Bergwelt-Baildon M, Bloch W (2016) Physical exercise modulates the homeostasis of human regulatory T cells. J Allergy Clin Immunol 137(1607–1610):e1608. doi:10.​1016/​j.​jaci.​2015.​10.​035
go back to reference Wilson LD, Zaldivar FP, Schwindt CD, Wang-Rodriguez J, Cooper DM (2009) Circulating T-regulatory cells, exercise and the elite adolescent swimmer. Pediatr Exerc Sci 21:305–317CrossRefPubMedPubMedCentral Wilson LD, Zaldivar FP, Schwindt CD, Wang-Rodriguez J, Cooper DM (2009) Circulating T-regulatory cells, exercise and the elite adolescent swimmer. Pediatr Exerc Sci 21:305–317CrossRefPubMedPubMedCentral
Metadata
Title
T-regulatory cells exhibit a biphasic response to prolonged endurance exercise in humans
Authors
Tom Clifford
Matthew J. Wood
Philip Stocks
Glyn Howatson
Emma J. Stevenson
Catharien M. U. Hilkens
Publication date
01-08-2017
Publisher
Springer Berlin Heidelberg
Published in
European Journal of Applied Physiology / Issue 8/2017
Print ISSN: 1439-6319
Electronic ISSN: 1439-6327
DOI
https://doi.org/10.1007/s00421-017-3667-0

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