Exercise-induced redistribution of T lymphocytes is regulated by adrenergic mechanisms

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Abstract

Acute exercise is known for causing considerable changes in leukocyte counts and function. In this paper we report that differentiated changes in T-lymphocyte distribution occur in lymphoid and non-lymphoid organs depending on the type and the intensity of exercise. Using fluorescent cell tracking we observed a release of T-cells from the spleen while lung, bone marrow and Peyer’s patches served as target organs. The number of T-cells in the blood rose after intensive running while lymphopenia occurred after swimming exercise. Changes in number of labelled T-cells were neither found in the lymph nodes nor in the thymus regardless of exercise protocol. Following an α- or β-blockade, the exercise-induced release of T-cells from the spleen and the accumulation of T-cells in the lung were inhibited while the enhancement of T-cells in the Peyer’s patches was not affected. The administration of epinephrine partially mimicked the effects of exercise and resulted in a release of T-cells from both, the spleen and the liver, as well as in an increase of circulating blood T-cells.

In conclusion, exercise induces a substantial re-distribution of T-cells within lymphoid and non-lymphoid organs. The migrating properties of T-cells could be partially explained by adrenergic mechanisms associated with exercise while the involvement of certain homing receptors remains to be shown. Our results suggest that the accumulation of T-cells in both, lung and Peyer’s patches, may enhance the immune vigilance in these compartments which serve as the body’s major defence barriers.

Introduction

The neuroendocrine and the immune system work together in homeostatic regulation to maintain health and to prevent diseases. Various forms of stress including physical and psychological stress can disrupt these systems by altering the concentrations of neurotransmitters, hormones or cytokines. Exercise is an important physical stress factor and is able to induce an inflammation-like state whose grade depends on type, intensity and duration of the activity (Hoffman-Goetz and Pedersen, 1994, Mooren et al., 2004).

Exercise is followed by an intensity-dependent increase of sympathetic activity as well as of the activation of the hypothalamo-pituitary axis leading to a systemic secretion of catecholamines (Ottavini and Franceschi, 1996). The release of epinephrine (E) and norepinephrine (NE) influences various immunological processes including lymphocyte proliferation, differentiation, cytokine production and the pattern of the circulation (Benschop et al., 1993, Sanders et al., 2004). T-lymphocytes respond to catecholamines via α- and β-adrenoceptors which are expressed on the cell surface (Madden and Felten, 1995). Thus, the relative effects of catecholamines are determined by the types and quantity of receptors present on target cells as well as by the local concentration of E and NE in their environment. Moreover there is evidence that catecholamines play a role in exercise-induced alterations in leukocyte counts since Kappel et al. (1991) found statistical correlations between concentrations of stress hormones and lymphocyte numbers in the blood during exercise.

Neutrophil concentrations increase during exercise and in the post-exercise period whereas lymphocyte counts increase during exercise and fall below pre-exercise values after intensive exercise or exercise with long duration (McCarthy and Dale, 1988, Pedersen and Toft, 2000). The alterations in blood lymphocyte counts may be the result of three different processes namely cell proliferation, cell death or cell traffic. Exercise has been shown an effect on lymphocyte proliferation (Nielsen and Pedersen, 1997). However, it seems unlikely that accounts for the short-lived changes in lymphocyte counts during and after exercise. Furthermore, we and others have shown that one reason for exercise-induced peripheral lymphopenia is programmed cell death or apoptosis (Mars et al., 1998, Mooren et al., 2002). In this case a loss of immunological competence cannot be excluded, which might be responsible for the higher incidence of upper respiratory tract infections after strenuous prolonged physical exercise as reported in some studies (Nieman, 1997). Finally, little is known about the effects of exercise on lymphocyte trafficking.

Lymphocyte traffic between the various body compartments is critical for the efficiency of the immune system. Lymphocytes migrate into lymphoid and non-lymphoid organs in order to scan the whole body for non-self antigens as well as to promote cell-to-cell interactions which are necessary to generate an adequate immune response. The various immune functions are compartmentalized into antigen presentation, activation and differentiation occuring in secondary lymphoid organs (Mackay, 1991, Butcher and Picker, 1996). However, not only can antigenic challenges substantially alter the distribution pattern of immune cells within the body. Instead the migration of lymphocytes is selective and includes a complex pattern of recirculation under different physiological and inflammatory conditions (Dhabhar et al., 1995).

The present study was designed to investigate the recirculation pattern of lymphocytes under conditions of different types and intensities of exercise in mice. In a further experiment we exercised mice after a treatment with α- and β-adrenergic receptor antagonists to investigate the role of catecholamines in lymphocyte redistribution after exercise. Finally we investigated whether the administration of epinephrine (E) and norepinephrine (NE) at concentrations occurring during intensive exercise could mimic the exercise-induced redistribution of lymphocytes. We hypothesize that exercise-induced changes of blood lymphocyte numbers are caused by a different redistribution of immune cells between the lymphoid and non-lymphoid organs. Furthermore, we assume that this redistribution is affected by exercise intensity and is regulated in some part by adrenergic mechanisms.

Section snippets

Experimental animals

This work was performed on 165 male SWISS-mice, age 6–8 weeks and weight 29.5 ± 2.5 g, bred at the animal facility of the UKM (University Hospital Muenster). Mice were randomized into 8 groups (n = 10). All animals were housed four per cage at 21 ± 1 °C in standard cages (29.5 × 18.5 × 12.5 cm) and had ad libitum access to food and tap-water. All experiments were approved by the Local Animal Care and Use.

Aerobic capacity

By using a treadmill spiroergometry (custom made), maximal oxygen uptake (VO2max) and maximal running

Distribution of fluorescent labelled lymphocytes under resting conditions

Twenty-four hours after adoptive cell transfer the resting distribution of CTG-labelled lymphocytes was investigated. Qualitative distribution of labelled cells was determined in tissue thin sections using fluorescence microscopy while flow-cytometry of tissue suspensions was used for quantitative investigation.

In general, labelled cells in lymphoid organs were found regionally localized in the expected T cell areas while in the non lymphoid tissues cells were homogenously distributed.

About 83%

Discussion

In recent studies lymphocyte homing and recirculation have usually been investigated by using radioactive tracers and metabolic labelling methods (Zatz and Lance, 1970, Smith and Ford, 1983, Constantin et al., 1997, Stefanski et al., 2003), whereas we used fluorescence microscopy and flow cytometry. Due to these different approaches a comparison has to be performed carefully. Constantin et al. (1997) detected highest percentages of radioactivity in spleen and liver of donor mice 24 h after

Acknowledgments

This study was financially supported by the Innovative Medizinische Forschung (IMF, # MO110511) of the Medical Faculty, University of Muenster. The authors gratefully acknowledge the assistance of Dr. Albert Fromme.

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