T-cells and their cytokine production: The anti-inflammatory and immunosuppressive effects of strenuous exercise

Cytokine 104 (2018) 136–142

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Review article

T-cells and their cytokine production: The anti-inflammatory and immunosuppressive effects of strenuous exercise

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David M. Shawa, , Fabrice Merienb, Andrea Braakhuisc, Deborah Dulsona a b c

Sports Performance Research Institute New Zealand (SPRINZ), Auckland University of Technology, Auckland, New Zealand AUT Roche Diagnostics Laboratory, School of Science, Auckland University of Technology, Auckland, New Zealand Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

A R T I C L E I N F O

A B S T R A C T

Keywords: Exercise T lymphocytes T-cells Cytokines Inflammation Immunity

Strenuous exercise bouts and heavy training are associated with a heightened anti-inflammatory state and a transient suppression of several immune components. In turn, many athletes are susceptible to illness, particularly upper respiratory symptoms (e.g. cough, sore throat, running nose). T-lymphocytes (T-cells) are important for orchestrating the immune response and can be categorised into subsets according to their phenotypical characteristics resulting from polarisation (i.e. type-1, type-2 and regulatory T-cells). Each T-cell subset has a unique functional role, including their capacity to produce pro- and anti-inflammatory cytokines in response to an immune challenge. Prolonged and exhaustive exercise typically reduces peripheral blood type-1 Tcell number and their capacity to produce the pro-inflammatory cytokine, interferon-γ. Moreover, heavy training loads are associated with elevated numbers of resting peripheral blood type-2 and regulatory T-cells, which characteristically produce the anti-inflammatory cytokines, interleukin-4 and interleukin-10, respectively. This appears to increase the risk of upper respiratory symptoms, potentially due to the cross-regulatory effect of interleukin-4 on interferon-γ production and immunosuppressive action of IL-10. Catecholamines significantly influence the number of peripheral blood T-cells in response to exercise. Whereas, glucocorticoids and prostaglandin E2 promote the production of anti-inflammatory cytokines by T-cells. In summary, strenuous exercise bouts and heavy training shifts T-cell immunity towards an anti-inflammatory state. This impairs the ability of the immune system to mount an inflammatory response to an immune challenge, which may weaken defences against intracellular pathogens (e.g. viruses), and increase the risk of infection and viral reactivation.

1. Introduction Athletes are perennially balancing their training load with recovery to optimise performance whilst preventing illness. In contrast to a large proportion of the general population who engage in low-to-moderate levels of physical activity and are at risk of chronic low-grade inflammation, athletes may be susceptible to a heightened anti-inflammatory state. This results from acute and repeated bouts of strenuous exercise, which can transiently suppress immune function and increase the risk of opportunistic infection by viruses and bacteria and viral reactivation. Upper respiratory symptoms (URS) (e.g. cough, sore throat, running nose) are the most commonly reported illness in athletes [1], with recurrent episodes compromising training availability [2] and performance at pinnacle events [3]. T lymphocytes (T-cells) play a pivotal role in the orchestration of the immune response and are currently considered a subclinical immune marker of medium suitability within immunonutrition and exercise investigations [4]. T-cells

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can polarise into various effector and regulatory cell subsets with divergent functional capacities to eliminate or neutralise pathogens, whilst preventing an overshooting of the immune response to harmless microbes [5]. They mediate other cells of the innate and acquired immune systems by producing specific pro- and anti-inflammatory cytokines [5]. Therefore, the purpose of this narrative review is to describe the effect of strenuous exercise on peripheral blood T-cell subsets and their capacity to produce their signature cytokine. Google Scholar, Scopus and key references from publications were searched using search terms (Exercise, T Lymphocytes, T-cells, cytokines, inflammation, immunity), with no date restriction and only articles in English were considered. Included studies were restricted to exercise at or above 70% VO2max and/or for periods of 60 min or longer, as well as periods of heavy training, within healthy populations. Furthermore, regulatory factors and the clinical implications of exercise-induced perturbations to T-cell immunity will be explored.

Corresponding author at: 17 Antares Place, Second Floor, Sports Performance Research Institute of NZ, Auckland 0632, New Zealand. E-mail addresses: [email protected] (D.M. Shaw), [email protected] (F. Merien), [email protected] (A. Braakhuis), [email protected] (D. Dulson).

http://dx.doi.org/10.1016/j.cyto.2017.10.001 Received 19 September 2017; Accepted 2 October 2017 Available online 08 October 2017 1043-4666/ © 2017 Elsevier Ltd. All rights reserved.

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rises (i.e. mobilisation), followed (within ∼30–60 min) by a decline to below pre-exercise levels (redeployment + apoptosis). Originally, researchers speculated that an exercise-induced reduction in peripheral blood immune cell counts indicated immunodepression. More recently, immune cell redistribution is suggested to contribute to immune surveillance and cytotoxicity in the peripheries [15]. These cell trafficking patterns originate in the marginated leukocyte pool, lymph nodes, spleen and bone marrow, and move via the blood stream to peripheral tissues (e.g. urogenital tract, skin, gastrointestinal tract, mucosal linings and respiratory tract) where contact with a pathogen is more likely to occur [15]. However, recent research has demonstrated that the skin is not a favoured site of relocation for T-cells [16].

2. T-cells and T-cell subsets 2.1. Helper and cytotoxic T-cells Lymphocytes comprise ∼20–25% of the leukocyte population in peripheral blood, of which, ∼60–80% are T-cells (CD3+ cells). T-cells are divided into helper T-cell (∼70%) and cytotoxic T-cell subsets during maturation in the thymus and are identified by their cluster of differentiation (CD) membrane co-receptors CD4+ and CD8+, respectively. CD4+ cells have a role in regulating both the cell-mediated and humoral arm of the immune response through cytokine signalling [5]. Alternatively, CD8+ cells are predominantly responsible for destroying virally infected cells and some tumour cells. CD8+ cells are not typically recognised for their regulatory function, however, they also produce cytokines [6].

3.1. Helper and cytotoxic T-cells 3.1.1. Acute exercise The level of peripheral blood CD4+ and CD8+ T-cells in the blood is proportionate to exercise intensity [17]. A larger number of CD4+ Tcells mobilise compared to CD8+ T-cells secondary to their dominance of the T-cell population. Nevertheless, there is a larger relative increase in CD8+ T-cells due to their higher density of β2-adrenoceptors and, therefore, the CD4+/CD8+ ratio is reduced. This movement of CD4+ and CD8+ T-cells into the blood augments when exercise has been performed earlier on the same day [18] and when exercise intensity is above (+15%), compared to below (−5%), lactate threshold [17]. When the recovery period between exercise bouts are shortened (3 vs 6 hours), CD4+ and CD8+ T-cells may fail to return to baseline levels [19]. This is followed by a greater exercise-induced increase in CD8+ Tcells, whereas CD4+ T-cells rise in a similar magnitude following both recovery periods [19].

2.2. Type-1 and type-2 T-cells T-helper and cytotoxic T-cells can polarise into type-1 or type-2 subsets, however, it is the cytokine production by the CD4+ T-cell population that is most responsible for immune regulation [7]. Type-1 T-cells are predominantly involved in cell-mediated immunity to combat intracellular pathogens, such as viruses. They are partially characterised by their production of the pro-inflammatory cytokine, interferon (IFN)-γ, and can activate CD8+ T-cells, natural killer (NK) cells and phagocytes [8]. Production of IL-12 by antigen presenting cells (APC) of the innate immune system, in conjunction with IFN-γ by NK cells and T-cells, polarise T-cells towards a type-1 phenotype in a feed-forward fashion [8]. T-box transcription factor (T-bet) programs the polarisation of the cell towards a type-1 phenotype by acting as a promoter of IFN-γ expression [9]. A reduction in the capacity to produce IFN-γ has been hypothesised to increase the risk of infection [10]. Conversely, type-2 T-cells are predominantly involved in humoral immunity, which provides protection against extra-cellular pathogens, particularly of bacterial and fungal origin [8]. They are partially characterised by their production of the anti-inflammatory cytokine, IL4, and can assist B-cells in upregulating the production of some immunoglobulins (e.g. IgE) and recruit eosinophils. IL-4 is antagonistic to IFN-γ and polarises T-cells towards a type-2 phenotype via the action of the transcription factor, GATA-3 [11].

3.1.2. Training Several days of intensified training can affect the level of peripheral blood lymphocytes and T-cells at rest and following acute exercise. In 18 untrained men (VO2max ∼ 46 ml·kg·min−1), there was a greater reduction of T-cells and lymphocytes after three days of cycling at 65% VO2max for one hour [20], whereas CD8+ T-cell count remained unchanged [20]. Other studies have shown exercise-induced CD4+ [21] and CD8+ [22] T-cell mobilisation and redeployment can be truncated following 6–7 days of intensified training in trained male cyclists (VO2max ∼ 64 ml·kg·min−1). However, periods of intensified training do not appear to effect exercise-induced lymphocytosis and lymphopenia [21,23]. During several months of Ironman triathlon training, the resting CD4+ and CD8+ proportion of peripheral blood T-cells remained unchanged [24]. Altogether, it seems that sharp increases in training load restricts T-cell trafficking patterns, which may impair immune surveillance and defence in peripheral tissues.

2.3. Regulatory T-cells Regulatory T (Treg)-cells represent 5–10% of the peripheral blood CD4+ T-cell population. They play a central role in modulating various immune responses and silencing self-reactive T-cells [12]. Treg cells express the cell surface marker CD25+, however, more specific markers are the intracellular expression of Forkhead transcription factor (FoxP3) and cell surface marker CD127low/− [12,13]. Naturally occurring CD4+CD25+ Treg (nTreg) cells (produced in the thymus) and transforming growth factor (TGF)-β induced Treg (iTreg) cells (produced in the periphery) are the two major types of Treg cells [12]. Treg cells suppress the activation, proliferation and effector functions of CD4+ (type-1 and type-2 T-cells), CD8+ cells, NK cells, dendritic cells, and Bcells primarily through the release of IL-10, an anti-inflammatory cytokine [12]. Although other T-cell subsets have been researched in an exercise context, including Th17 cells and gammadelta T-cells, there is a paucity of evidence describing their cytokine production and, therefore, they will be excluded from this review.

3.2. Type-1 and type-2 T-cells 3.2.1. Acute exercise Strenuous exercise reduces peripheral blood type-1 (IFN-γ+) CD4+ and CD8+ T-cells (Fig. 1). For example, immediately following 150 min of running at 75% VO2max, the percentage of mitogen stimulated IFNγ+CD4+ and IFN-γ+CD8+ T-cells (of total T-cells) declines in trained men (VO2max ∼ 52–68 ml·kg·min−1) [25]. This reduction was sustained for up to 24 hours post exercise. Conversely, there was no change in the percentage of mitogen stimulated type-2 (IL-4+) CD4+ and CD8+ Tcells [25]. These findings have been corroborated in whole blood mitogen stimulated cultures showing both a reduction in the number and percentage of IFN-γ+ T-cells, without an alteration in IL-4+ T-cells immediately and one hour following cycling to exhaustion at ∼74% VO2max (107 ± 7 min) [26]. Furthermore, some studies report an increase or no change in stimulated IFN-γ+ T-cells immediately following exercise, however, these typically decline to below pre-exercise levels within two hours into recovery [23,27,28]. Other studies have shown

3. Effect of strenuous exercise on peripheral blood T-cell number Peripheral blood lymphocytes elicit a biphasic response to exercise proportionate to the intensity and, to a lesser extent, duration [14]. During and immediately following exercise, the number of lymphocytes 137

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Fig. 1. Changes in peripheral blood T-cell subset number relative to baseline values in response to a strenuous exercise bout. CD4+ cell T-helper cell, CD8+ cell Cytotoxic cell, Treg cell Regulatory T-cell, Th1 cell Type-1 T-helper cell, Th2 cell Type-2 T-helper cell, Tc1 cell Type-1 Cytotoxic T-cell, Tc2 cell Type-2 Cytotoxic T-cell.

an increase in both unstimulated IFN-γ+CD8+ and IL-4+CD8+ T-cells [17,29] and IFN-γ+ and IL-4+ T-cells [30] following shorter exercise bouts (30–60 min). However, exercise-induced increases in T-cells expressing these cytokines does not necessarily persist after stimulation [29]. Altogether, the reduction in peripheral blood type-1 T-cells is likely due to a combination of redistribution to peripheral tissues and polarisation favouring a shift towards type-2 T-cells, which may dampen the inflammatory response to an immune challenge and increase the risk of infection and viral reactivation.

reduction may be due to apoptosis [32] or redistribution of cells to peripheral tissues. Interestingly, in a recent study, CD4+CD25++FoxP3+ T-cell number and percentage of CD4+ cells initially declined one hour into recovery, then increased above baseline values one day after a marathon, indicating a biphasic response of these anti-inflammatory and immunosuppressive T-cells [38]. 3.3.2. Training More consistent findings in peripheral blood Treg cell number have been linked with heavy training loads [36,39–41]. In particular, individuals involved in sports where aerobic capacity is an importance factor for performance appear to have elevated Treg cell counts [40]. Conversely, one study reported reduced CD4+CD25+FoxP3+ T-cell percentage of PBMCs in marathon trained individuals, although, this discrepancy was resolved when adjusted for body mass index [31]. In the same study, there was also a higher percentage (of PBMCs) of IL10+CD4+ and TGF-β+CD4+ T-cell subsets in the marathon trained group [31]. Furthermore, another study showed no effect of eight days intensified training on CD4+CD25+CD127low/− T-cells in trained individuals, which is unsurprising given this population may have already had a relatively enlarged Treg cell population [21]. Considering Treg cells preferentially produce the anti-inflammatory and immunosuppressive cytokine, IL-10, heavy training loads are likely to promote immunosuppression and increase infection risk.

3.2.2. Training Several days of intensified training influences the number and trafficking pattern of peripheral blood IFN-γ+ T-cells, but not IL-4+ Tcells. For example, seven days of intensified training reduced the number of IFN-γ+ T-cells at rest [26]. Additionally, IFN-γ+ T-cells didn’t significantly change during, immediately after and one hour after a cycling bout to exhaustion at ∼74% VO2max (85 ± 5 min) [26]. This contrasts to when the same participants cycled to exhaustion at the same intensity following a normal training volume [26]. Additionally, lower IFN-y+CD4+ and higher IL-4+CD4+ T-cell percentage of peripheral blood mononuclear cells (PBMCs) have been demonstrated in marathon trained individuals [31]. This preferred accumulation of antiinflammatory, type-2 T-cells and failure of type-1 T-cells to effectively relocate to peripheral tissues in response to an exercise bout suggests periods of heavy training may reduce cytotoxicity in peripheral tissues and increase the risk of infection and viral reactivation.

4. Effect of strenuous exercise on peripheral blood T-cell cytokine production

3.3. Regulatory T-cells 4.1. Measurement of cytokine production 3.3.1. Acute exercise Strenuous exercise has demonstrated equivocal effects on peripheral blood Treg cell number immediately following exercise (Fig. 1). This may be underpinned by the intensity and duration of the exercise bout. For example, shorter exercise bouts requiring near maximal power outputs appear to increase CD4+CD25+CD127low/− [21,32] and CD4+CD25+FoxP3+ T-cell number [33], with females showing a higher increase once adjusted for baseline values [33]. However, the relative contribution of Treg cells to the CD4+ cell population may actually decline [34]. In contrast, longer duration submaximal exercise may not effect CD4+CD25+CD127low/− T-cell number and concentration [35,36], or percentage of total lymphocytes [35,36] and CD4+ Tcells [36]. Although, two studies have demonstrated a reduction in CD4+CD25+FoxP3+ T-cell number and percentage of total CD4+ Tcells following a half ironman triathlon and marathon [37,38]. This

Typically, T-cells are stimulated in vitro with an immunogenic agent, such as such mitogens, superantigens, specific-(multi-)antigens or antiCD3+ antibodies. Each agent has a unique immunogenicity which elicits a different cytokine response. The cellular, hormonal, cytokine and substrate make-up of the culture also influences the T-cell response during the incubation (stimulation) period. Furthermore, the duration of the incubation period is variable, lasting from ∼1 hour (pulse stimulation) to several days. Different time points are associated with cytokine-specific changes in concentration resulting from their unique rates of production and utilisation. Whether findings from these analytical techniques are clinically meaningful is arguable, however, it has been suggested that using whole blood specific-antigen cultures may be more representative of an in vivo immune challenge than isolated cell cultures using mitogenic stimulation. 138

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Nevertheless, IFN-γ mRNA expression within PBMCs was not altered, suggesting T-bet had no effect on cytokine regulation (IL-4 mRNA was not measured) [43]. Another study showed unstimulated mRNA expression of Tbet was unaltered, whereas GATA-3 mRNA was increased 10 days after the completion of a marathon (249 ± 46.5 min), which coincided with an increase in IL-4 mRNA (no change to IFN-γ mRNA) [44]. This latter finding corroborates with the concept that strenuous exercise favours type-2 immunity. Nevertheless, more research is required to fully elucidate the mechanisms underpinning T-bet and GATA-3 regulation on cytokine gene expression. Arguably, more clinically meaningful findings are ascertained using whole blood, specific-antigen stimulation protocols, as this is more reflective of an in vivo immune challenge. However, studies using acute exercise protocols 90 min or less have often failed to produce significant findings [21,35,45]. Nonetheless, immediately following 120 min cycling at 60% VO2max, multi-antigen stimulated whole blood production of IFN-γ declined, with no change to IL-4 production, which persisted for two hours into recovery within healthy males (VO2max ∼ 58 ml·kg·min−1) [46], suggesting a suppression in type-1 immunity. Since the number of peripheral blood IFN-γ+ T-cells was not measured, it is difficult to conclusively state whether this was specifically due to a decline in IFN-γ+ T-cells or a reduction in their capacity to produce IFN-γ, or both.

The level of cytokines within the culture supernatant is normally measured using ELISAs or cytometric bead array. Some studies also adjust for changes in cytokine concentration to a per cell basis, presuming the selected cell is the major contributor of the cytokine. Alternatively, an intracellular protein transport inhibitor can be added to the culture to allow for the measurement of intracellular cytokine production using flow cytometry. The cytokine transcriptional capacity of T-cells relative to at least two housekeeping genes can also be measured using polymerase chain reaction and is suggestive of immune activation. Similarly, quantifying the magnitude of expression for cognate transcription factors governing the differentiation of T-cells can also provide insight into the mechanisms underpinning the production of their cytokines. Due to the methodological heterogeneity and numerous analytical issues, definitive conclusions should be made with caution. It is also generally accepted that the in vitro immune response is unlikely to reciprocate the complexities of an in vivo response and, therefore, increases the risk of artefacts and misinterpretations. 4.2. Interferon-γ and interleukin-4 4.2.1. Acute exercise Strenuous exercise typically results in a reduced capacity of peripheral blood T-cells to produce IFN-γ immediately following exercise (Fig. 2). This has been demonstrated within numerous studies using stimulated PBMC and whole blood cultures [42]. Several studies have also reported impaired IFN-γ production in the hours following exercise [42]. Conversely, T-cell capacity to produce IL-4 appears unaffected. Interestingly, the changes in type-1 or type-2 T-cell number do not always parallel their capacity to produce their signature cytokines. Whilst some studies have demonstrated reductions in mitogen stimulated IFNγ+ T-cell levels coinciding with lower intracellular expression of IFN-γ immediately post exercise [23,26], others have reported an increased number of IFN-γ+ T-cells despite a reduction of mitogen stimulated IFN-γ production per T-cell [27]. This may be due to cell trafficking patterns, with exercise priming the mobilisation of T-cells that are known to preferentially produce IFN-γ, but have a lower capacity to produce IFN-γ. Nevertheless, it appears conclusive that prolonged, exhaustive exercise elicits a reduction in T-cell IFN-γ production. This is likely to attenuate the inflammatory response of type-1 immunity and increase the risk of infection and viral reactivation. The transcriptional factors T-bet and GATA-3 may help to explain changes in cytokine production. For example, following one hour of cycling at 70% VO2max in trained males (VO2max ∼ 62 ml·kg·min−1), Tbet and GATA-3 mRNA expression increased in unstimulated PBMCs [43], suggesting an enhanced type-1 and type-2 immune response.

4.2.2. Training Following several days of intensive training, the suppressive effect of strenuous exercise on mitogen stimulated T-cell IFN-γ production persists without an alteration to IL-4 production [26]. Whereas, several days of intensified training does not appear to influence the effect of strenuous exercise on multi-antigen stimulated, whole blood production of IFN-γ and IL-4 [21]. Alternatively, heavy training loads are associated with a higher resting multi-antigen stimulated, whole blood IL4 production and an increased risk of URS when compared to low training loads [39,47], indicating heavy training favours type-2 immunity. 4.3. Interleukin-10 4.3.1. Acute exercise The influence of acute exercise on T-cell IL-10 production is equivocal (Fig. 2). In stimulated whole blood and PBMC cultures, IL-10 production either increases [46,48–50], decreases [51,52] or does not change [21,35,53]. Furthermore, unstimulated FoxP3 mRNA expression did not change within PBMCs following one hour of cycling at 70% VO2max [43]. However, it is difficult to compare these studies due to the different exercise protocols and analytical techniques.

Fig. 2. Changes in peripheral blood T-cell capacity to produce their characterising cytokine in response to a strenuous exercise bout. Treg cell Regulatory T-cell, IFN-γ Interferon-gamma, IL-4 Interleukin-4, IL-10 Interleukin-10.

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T-cell, CD4+ and CD8+ cell number [58,69]. It has been speculated that this results from increased blood flow and mobilisation from the blood vessels of the marginalised pools [68]. However, the use of a βantagonist (propranolol) for a week prior to exercise reduced the increase in lymphocytes, CD4+ and CD8+ cells, without affecting the rise in catecholamines [70], suggesting an alternative or additional reason underpinning lymphocytosis. Speculatively, lymphocytes may also be released from the spleen via activation of β-adrenoceptors [71]. It has been previously suggested that periods of intensified training reduces β2-adrenoceptor sensitivity on lymphocytes, which helps to explain the dampened mobilisation and redeployment of CD8+ cells [22]. In vitro models suggest glucocorticoids and catecholamines have a synergistic effect on T-cell cytokine production [67]. Adrenaline and, to a lesser extent, noradrenaline suppress IFN-γ production and enhance IL-4 and IL-10 production by PBMCs in a dose dependent manner [72]. Similarly, in whole blood cultures, epinephrine concentrations at 1 nmol·L−1 reduced IL-12 production by ∼50%, with 5 nmol·L−1 reducing IL-12 to undetectable levels [61]. Inversely, epinephrine increased the production of IL-10 in dose dependent manner, particularly at levels above 1 nmol·L−1 [61]. Nevertheless, not all studies suggest catecholamines influence T-cell cytokine production [68], which may be due to a dose response. Additionally, when six endurance trained men cycled for ∼19 min at ∼78% VO2max, the intake of an α- and βadrenoceptor blockade abrogated the effect of only lymphocyte trafficking, not the magnitude of IFN-γ or IL-2 production by lymphocytes in mitogen stimulated whole blood cultures [27]. This suggests catecholamines don’t effect cytokine production during exercise. Treg cell function is also mediated by activation of β2-adrenoceptors in murine [73] and human [66] in vitro cultures, but exercise specific effects are unclear. Altogether, it appears that catecholamines have a role in T-cell trafficking, however, their effect on cytokine production at physiological levels is uncertain.

4.3.2. Training High compared to low training loads are associated with a higher multi-antigen stimulated, whole blood IL-10 production [36,39]. This elevated capacity to produce IL-10 is associated with higher circulating Treg cell levels [36], elevated whole-blood, multi-antigen stimulated IL4 production [47], lower salivary immunoglobulin A secretion rate and concentration [47], and increased URS incidence [47]. Altogether, it appears there is a heightened anti-inflammatory response to an immune challenge when engaging in high training loads, which favours a suppression of type-1 immunity and may weaken defences against infection, particularly viruses, and viral reactivation. 5. Potential role of stress hormones and prostaglandin E2 on T cell number and function 5.1. Glucocorticoids The plasma concentrations of cortisol rise proportionately to exercise duration [54] and most markedly when exercise intensity is > 60% VO2max [55]. Following periods of intensified training, the exercise-induced rise in cortisol is truncated [26]. Unlike catecholamines, which decline swiftly following exercise cessation, cortisol can exert its immunological effect over several hours [54]. The administration of hydrocortisone (synthetic cortisol) causes lymphopenia, which can be partly attributed to decline in T-cells [56,57]. Nevertheless, this response only occurs when cortisol reached concentrations above exercise-induced concentrations (i.e. ∼1400 nmol·L−1) [56]. The effects of exercise-induced rises in cortisol on individual T-cell subset number is obscure, however, it may explain some variation in CD4+ T-cell number [58]. Additionally, carbohydrate intake during exercise tends to reduce the rise in cortisol, which can occur simultaneously with an attenuated reduction in IFN-γ+CD4+ and IFN-γ+CD8+ cells, and their IFN-γ production following two hours of cycling at 65% VO2max in a group of seven moderately to well-trained men (VO2max ∼ 59 ml·kg·min−1) [23]. It remains uncertain if cortisol affects Treg cell number. In vitro models demonstrate that dexamethasone (a synthetic derivative of cortisol) [59–61] and supra-physiological levels of hydrocortisone [62] reduce the production of IL-12, a type-1 cytokine, by APCs. In turn, this can reduce the upregulation of IFN-γ and inhibition of IL-4 production by T-cells, favouring a type-2 immune response. Dexamethasone also appears to directly reduce IL-12 receptors on Tcells and NK cells, inhibiting their ability to produce IFN-γ. However, the shift towards a type-2 response is believed to be mainly through the reduced production of IL-12 by APCs [63]. Dexamethasone does not affect the production of IL-10 by monocytes, but does upregulate lymphocyte IL-10 production [61,64]. In CD4+ cells, exposure to dexamethasone increases IL-4 production and IL-4, IL-10 and IL-12 mRNA expression [64]. Additionally, some evidence demonstrates equivocal effects on FoxP3 expression and Treg cell function in human cells following incubation with dexamethasone [65,66]. It is important to note that dexamethasone’s immunological influence may differ compared to cortisol due to its greater anti-inflammatory effect. Nevertheless, the effects of glucocorticoids on T-cell function appears to favour a shift towards an anti-inflammatory cytokine response [67].

5.3. Prostaglandin E2 The plasma concentrations prostaglandin E2 (PGE2) increase during exercise. Specifically, PBMCs have been shown to increase their production of PGE2 by 3.5-fold following an acute bout of exercise [74] and the elevated concentration of plasma PGE2 may persist for up to two days [75]. PGE2 acts mainly via its G2-coupled receptors, EP2 and EP4, on leukocytes. Most studies demonstrating the influence of PGE2 on T-cell function have used in vitro models. PGE2 suppresses T-cell production of type-1 cytokines, IFN-γ and IL-2, whilst the type-2 cytokines, IL-4 and IL-5, are unaffected [76]. PGE2 indirectly affects CD4+ cells by reducing the production of IL-12 by monocytes and dendritic cells [77] and downregulating the expression of the IL-12 receptor in PBMCs and T-cells [63]. PGE2 also suppresses NK cell production of IFN-γ and IL-12 sensitivity [78]. Furthermore, PGE2 increases IL-10 production [63] and potentiates in vitro Treg cell induction and differentiation by upregulating the expression of FoxP3 [79]. Altogether, PGE2 appears to favour an anti-inflammatory T-cell cytokine response, which may increase the risk of infection and viral reactivation, nevertheless, further research is required to elucidate the effects of PGE2 on T-cells in an exercise context.

5.2. Catecholamines

6. Conclusion

The plasma concentrations of catecholamines of the sympathetic nervous system, adrenaline and noradrenaline, rise proportionately to exercise duration and exponentially with exercise intensity [54] and exert their function largely via β-adrenoceptors on leukocytes [54]. The majority of studies have shown the effects of adrenaline and βagonist (isoproterenol) infusion on CD4+ and CD8+ cells is equivocal [68]. Exercise-induced elevations in plasma adrenaline is positively associated with lymphocyte number, and may explain some variation in

Strenuous exercise bouts and heavy training loads elicit an anti-inflammatory effect on peripheral blood T-cell subset numbers and their capacity to produce key cytokines in response to an immune challenge. This is not synonymous with the general population who primarily engage in low-to-moderate levels of physical activity and are at an increased risk of being within a pro-inflammatory state. In particular, the number of peripheral blood type-1 T-cells and their capacity to produce IFN-γ decline either immediately following an exhaustive exercise bout 140

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