Abstract
The objective of this review is to illustrate how frequent strenuous exercise and heavy training are associated with immunosuppression as in susceptibility to infections and illnesses. Many people who are active are also vulnerable to the upper respiratory illnesses (e.g. sore throat, running nose). The common lymphoid progenitor is playing an essential key role in regulating the immune response. In particular, T-lymphocytes (T-cells) are mature cells within the common lymphoid progenitor which are important for controlling the immune system and can be divided in many subsets (e.g., type I [TH1], type II [TH2]). Each subset has a specific functional role such as pro- or anti-inflammatory cytokines in the event of immunocompromise. Prolonged and heavy exercise typically reduces certain types of T-lymphocytes which increased other products that associate with an elevated risk of upper respiratory tract infection.
Keywords: exercise, cytokines, inflammatory, T-lymphocytes, subsets
Introduction
Inflammation, the body’s complex biological reaction to damaging stimuli, is an essential response of the immune system to infection or trauma. Professional athletes are trained to balance their workload and recovery phase to maximize their performance while preventing illness. However, many athletes are still at risk of low to moderate inflammatory state. This results from frequent strenuous exercise with heavy loads which can subsequently suppress the immune system and enhance virulence factors of many opportunistic pathogens. T-cells are important in regulating immune responses. In addition, T-cells are capable of dividing into different subsets which diverge in functional capacities to neutralize or lysing pathogens while preventing an overshooting of the immune response to harmless microbes.1 They also regulate other cell lines of the innate and acquired immune systems by producing specific pro- and anti-inflammatory cytokines.1 Cytokines produced by T lymphocytes play a critical role in the development of host immunity against infection. It has been established that intracellular pathogens initiate a strong cellular immune response resulting in the differentiation of naive CD4+ and CD8+ T lymphocytes into type I T lymphocytes (Th1, cytotoxic T-cell type I). These cells are characterized by the production of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin-2 (IL-2). On the other hand, extracellular pathogens initiate a humoral immune response resulting in the differentiation of naive CD4+ and CD8+ T lymphocytes into type II T lymphocytes (Th2, cytotoxic T-cell type II), these cells are characterized by the production of IL-4, IL-5, etc. Given that the type I and type II balance is considered to be closely associated with the immune function in response to different forms of exercise, the purpose of this review is to describe the effect of prolonged and intense exercise on peripheral blood T-cells subsets, type I/type II balance and T-cell ability to produce their unique cytokines and ultimately put athletes at risk of inflammation and susceptible to infection and induced illness.

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Elevation of inflammatory mediators
The human body has been known for its efficiency of physical and chemical barrier in fighting against foreign pathogens. The physical barrier is the first defensive line which is skin formation. In the event when the first line of defense fails to do its job, the secondary defense will take the role by inducing inflammation mechanism. Inflammatory response is capable of releasing different indicators which help with diagnosing systemic of inflammation. The focus of this section will be C-reactive protein (CRP), an inflammatory biomarker concerning disease risk prediction.2 In addition to CRP, there are several others acute phase reactants, or plasma cytokines, such as interleukins and tumor necrosis factor, these cytokines are strongly associated with the risk of several diseases. Intensive training can affect the level of these plasma cytokines which may impair immune surveillance.
T-cells and T-cell subsets
Previous studies suggest that approximately 20-25% of white blood cell population are lymphocytes, of which, 65-85% are T-cells. T-cells later mature in the thymus which are helper T-cell and cytotoxic T-cell. These subsets are identified by their cluster of differentiation (CD) membrane co-receptors CD4+ and CD8+, respectively. CD4+ T-cells play a role in regulating both the cell-mediated and humoral immunity. Alternatively, CD8+ cells are specifically responsible for destroying virally infected cells and some tumor cells.
Effect of heavy exercise on lymphocyte population
In acute exercise, the level of T-cell population (CD4+ and CD8+) in peripheral blood is proportionate to the intensity of the exercise.3 A larger number of CD4+ T-cells
mobilize compared to CD8+ T-cells secondary to their dominance of the T-cell population. This movement of CD4+ and CD8+ T-cells into the blood augments when exercise intensity is above (+15%), compared to below (-5%), lactate threshold.3 The increased lymphocyte concentration is due to recruitment of all lymphocyte subpopulations to the peripheral blood. Thus, the CD4+ T-cells, CD8+ T-cells, natural killer (NK) cells increase in number during exercise and decline after intense exercise lasting at least a few hours. It is uncertain that CD4+ and CD8+ T-cells may return to their normal levels when athletes enter their recovery phase of the exercise.
Furthermore, after intense long duration exercise, the functions of NK are suppressed.4. Thus, the NK cell activity (the ability of NK cells to lyse a certain number of tumor target cells) is inhibited which could leave athletes vulnerable to pathogens. This phenomenon makes it clear that athletes who often have intense training are more susceptible to illness since many functions of NK cells are suppressed.
Effect of heavy exercise on T-cell cytokines production
In the immune system, all cells are capable of mobilizing themselves by recognizing and inhibiting certain chemicals. In particular, T-cells are stimulated in vitro with immunogenic agents. Each agent has unique immunogenicity which signals different cytokine responses. Cytokines are proteins that regulate immune function and inflammation. There are two types of cytokines, pro-inflammatory cytokines that promote inflammation and anti-inflammatory cytokines that attenuate inflammation following infection or injury.3 Type I responses are characterized by the production of interferon (IFN‐γ), whereas type II responses are dominated by IL‐4.3 Prolonged and heavy exercise generally results in a reduced capacity of peripheral blood T-cells to product IFN- γ immediately following exercise. Many studies have shown disagreements upon the level of these cytokines following strenuous exercise whether if the level of IFN-γ, IL-4would increase, decrease or unchanged. 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 I immunity and increase the risk of infection and viral reactivation.5
 In addition, type I and type II immunity concentrations balance and their functions in peripheral blood are further elucidated in this section since they also have acute effects after high-intensity exercise. There has been consistent evidence that both of the distribution and function of type I cells in the circulation are suppressed 1 hour after one bout of prolonged (1 hour or more) high-intensity exercise, whereas no significant changes are found in the distribution and function of type II cells.5 During a high-intensity exercise, the circulating concentration of type I cells can be affected more significantly by adrenalin and noradrenalin because there is a higher surface expression of β2-adrenergic receptors on type I cells compared with type II cells.5 It has been suggested that periods of intensified training reduces β2-adrenergic receptors sensitivity on lymphocytes, which helps to explain the dampened mobilization and redeployment of CD8+ cells. The suppression of the distribution and function of type I cells following prolonged high-intensity exercise may be associated with the changes of some hormones.
A class of hormones is introduced due to its core function in regulating cytokines which is glucocorticoids and catecholamines. Glucocorticoids (GCs) are a class of steroid hormones and they are part of the feedback mechanism in the immune system which reduces certain aspects of immune function, such as inflammation. Theoretically, glucocorticoids act through their classic cytoplasmic/nuclear receptors on antigen presenting cells (APCs) to inhibit the production of IL-12 that is the main inducer of Th1 cells. IL-12 is extremely potent in enhancing IFN-γ and inhibiting IL-4 synthesis by T cells. Therefore, GCs’ inhibition of IL-12 production may be a major mechanism by which GCs affect Th1/Th2 balance.5 Similarly, catecholamines (CAs) suppress the production of IL-12 and IFN-γ and stimulate the production of type II cytokines. The plasma concentrations of catecholamines of the sympathetic nervous system, adrenaline and noradrenaline, rise proportionally to exercise duration and exponentially with exercise intensity. Exercise-induced elevations in plasma adrenaline is positively associated with lymphocyte number, and may explain some variation in T-cell, CD4+ and CD8+ cell number.
Conclusion
Strenuous exercise 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 I T-cells and their capacity to produce IFN-γ decline either immediately following an exhaustive exercise or in the early stages of recovery, whereas type II T-cell number and their production of IL-4 appears unchanged. Furthermore, intense and heavy training loads result in the accumulation of type II T-cells and a reduction of type I T-cells. This impairs the ability of the immune system to produce an inflammatory response to an immune challenge and may reduce the protection against intracellular pathogens (e.g., viruses) and other potential diseases; the phenomenon is also called immunosuppression. Therefore, scientific training and appropriate dietary should be implemented to support immune function, especially in illness prone in athletes.
References

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E. C. LaVoy, M. Hussain, et al., T‐cell redeployment and intracellular cytokine expression following exercise: effects of exercise intensity and cytomegalovirus infection. Physiol Rep, 5 (2017), e13070, doi: 10.14814/phy2.13070
Crisafulli, Antonio, et al., Natural killer cells responsiveness to physical exercise: A brief review, Open Journal of Immunology 3 (2013) 190-193. doi: 10.4236/oji.2013.34024
Zhao, Guanggao, et al., Effects of moderate and high intensity exercise on T1/T2 balance, Exercise Immunology Review 18 (2012) 98-105

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629815/