Emerging data indicates that enrichment of peripheral blood with T lymphocytes during exercise and their associated changes in function are underpinned by modulation of cellular bioenergetics. However, there is a dearth of literature examining these responses using metabolic thresholds to prescribe exercise intensity or providing single cell resolution on immunometabolic outcome measures. The current study was designed to examine the metabolic phenotypes and real-time bioenergetic responses to activation of enriched naïve helper (CD4+) and cytotoxic (CD8+) T cells and peripheral blood mononuclear cells (PBMCs) in response to prolonged cycling. Tenaerobically trained males and females (mean ± SD: age 21±1 years; maximal oxygen consumption: 53.9 ± 9.8 ml · kg-1 · min-1) undertook a 2-hour bout of continuous cycling at a power output eliciting 95% lactate threshold-1. Blood samples were collected at rest, immediately (post), and 2 hours after cycling cessation (recovery). Using injection sequences of cell respiration modulators and a CD3/CD28 activator, bioenergetic profiles of PBMCs and enriched naïve CD4+ and CD8+ T cells were determined using extracellular flux analysis. Mitochondrial membrane potential (ΔΨm) was examined using flow cytometry. Despite cycling evoking significant fluctuations in peripheral blood T cell numbers, there were no changes in absolute or relative measures of mitochondrial respiration, glycolytic flux and ATP synthesis rate post and recovery vs rest. Contribution of mitochondrial respiration to ATP production was greater than glycolysis in naïve T cells across all timepoints, but not PBMCs in recovery. This was despite absolute and relative changes in ΔΨm of memory T cells being greater in recovery vs. rest. Bioenergetic responses to ex vivo T cell activation were not different between cell types or timepoints. These data indicate that the metabolic phenotypes of naïve T cells and PBMCs were largely unaltered within 2 hours of prolonged moderate intensity cycling.

Estimating the occurrence of acute respiratory illness (ARI) in athletes is crucial for understanding the need for preventive measures. This study aimed to estimate the occurrence of ARIs in athletes compared to non-athlete controls. We evaluated which of the published studies on the occurrence of ARI in athletes were eligible, giving due consideration to the epidemic nature of viral ARIs. We performed a systematic search of PubMed, EBSCOhost, and Web of Science databases from January 1990 to May 2023. Only studies reporting the occurrence of ARIs in athletes, with a duration of at least 12 months and simultaneously employing non-athlete controls, were included. The random effects model was used to calculate the incidence rate ratio (IRR) of ARI in athletes compared to non-athlete controls, with 95% confidence intervals. Our search yielded 218 results, of which 6 studies met the essential criteria for viral ARIs and were included in our metaanalysis. Since the exact number of ARIs was not reported in many studies, we had to estimate the total number of ARIs for both athletes and non-athlete controls. The occurrence of ARIs was 1.87 times higher in athletes compared to non-athlete controls (3.2 vs 1.7, pooled IRR 1.87, 95% CI 1.08 to 3.26). Publication bias analysis or a funnel plot was not evaluated because the primary objective of none of the studies was to determine the occurrence of ARI in athletes. Most of the studies on the occurrence of ARIs in athletes had a duration of less than 12 months and did not include a concurrent control group, making them ineligible considering the seasonal and contagious nature of ARIs. Our meta-analysis suggests that athletes suffer from significantly more ARIs than non-athletic subjects. Our observations highlighted the lack of high-quality long-term studies on the occurrence of ARIs in athletes.

In the pathogenesis of knee osteoarthritis (KOA), inflammatory mediators play an important role. However, the precise underlying mechanism by which regular exercise therapy (ET) exert effects on the immune system in KOA patients is unknown. The aim of this systematic review was to investigate the basal and acute effects of ET on inflammatory biomarkers and brain derived neurotrophic factor (BDNF) in KOA patients. PubMed, Web Of Science and PEDro were systematically searched for appropriate studies. If possible, a meta-analysis was performed or an approximation of the effect size (ES) was calculated. Risk of bias was scored using the Cochrane ROB 2.0 or ROBINS-tools. Twenty-one studies involving 1374 participants were included. Fifteen articles focused on basal exercise effects, four on acute effects, and two on both. Biomarker analysis (n=18) was performed in synovial fluid (n=4) or serum/plasma (n=17). A meta-analysis demonstrated that basal CRP was reduced in KOA patients 6-18 weeks weeks after ET (MD: -0.17;95%CI[-0.31;-0.03]), while IL-6 (MD: 0.21;95%CI[-0.44;0.85]), and TNF-α (MD: -0.57;95%CI[-1.47;0.32]), levels did not significantly change. Also, sTNFR1/2 did not change significantly after ET. For other biomarkers, insufficient data were available to perform a meta-analysis. Nevertheless, a low degree of evidence was found for a decrease in IL-6 (ES:-0.596 & -0.259 & -0.513), an increase in sTNFR1 (ES:2.325), a decrease in sTNFR2 (ES:-0.997) and an increase in BDNF (ES:1.412). Locally, intra-articular IL-10 (ES:9.163) increased, and IL1β (ES:-6.199) and TNF-α decreased (ES:-2.322) after ET. An acute exercise session elicited a myokine response (ES IL-6:0.314), and an increase in BDNF (no ES-data). No inflammatory effect (ES CRP:0.052; ES TNF-α:-0.019 & 0.081) following an acute bout of training was found. However, a single bout of exercise elicited a decrease in intra-articular IL-10 (no ES-data). ET can induce circulatory and intra-articular anti-inflammatory effects in patients with KOA. The antiinflammatory properties have important implications for informing these patients and clinicians about the underlying effects of ET.

Individuals who participate in regular exercise over time have a markedly reduced risk of cardiovascular disease. Paradoxically, in susceptible individuals with underlying, often undiagnosed, disease states, exercise may acutely increase an individual's risk of cardiovascular events during and immediately following physical exertion. Exercise is thought to evoke conditions that trigger atheromatous plaque rupture or trigger life threatening arrhythmias in individuals with pre-existing, vulnerable coronary artery and inherited cardiovascular disease respectively. This transient increased risk may be driven by the inflammatory trigger provided by physical exertion where exercise is associated with an upregulation of inflammatory mediators in the acute phase. Conversely, habitual exercise can lead to a modulation of the inflammatory response over time. This review explores: exercise related inflammation; acute cardiovascular events related to exercise and strategies to mitigate these risks.

Traumatic brain injury (TBI) is the largest cause of death and disability globally. The physical and psychosocial consequences after TBI can persist for prolonged periods, and lead to increased health care and economic burden. Exercise has shown promise over recent years as a mode of rehabilitation that alleviates multiple TBI symptoms; but there is a lack of controlled large-scale studies and limited research into the underlying mechanisms. This critical review draws from animal and human studies on exercise immunology to speculate on possible mechanisms that could underlie beneficial outcomes of exercise after TBI. The anti-inflammatory role of exercise, protective role offered by pre-injury exercise, and the need for more objective studies on biomarker analysis are expected to be useful considerations to develop optimal post-TBI exercise rehabilitation programs. Future studies can consider investigating the specific immunological processes induced by exercise in consideration of individual differences and non-aerobic exercise modalities.

Regular exercise, particularly moderate-intensity continuous training (MICT), can improve immune function. Natural killer (NK) cells, a subset of lymphocytes that react to infections, are the most responsive innate immune cells to exercise, but the mechanisms underlying this are poorly understood. A type of exercise training that is gaining popularity in recent years is high-intensity interval training (HIIT), but how it affects NK cells is largely unknown. In fact, intense exercise has been traditionally viewed as a potential stressor to immune homeostasis. The purpose of this study was to determine in healthy, previously untrained adults (N=8 [3 male; 40±6 years]) the effects of an intervention consisting of 4-week MICT followed by 4-week HIIT on NK cells as compared with a pre-training (baseline) state. Participants were studied at three time points: baseline, mid-intervention (after MICT), and post-intervention (after HIIT). Main assessments included cytotoxicity assays, flow-cytometry analysis of NK cell surface markers, and interrogation of the cellular proteome using a systems biology approach. A significant time effect was found for NK cell cytotoxicity (p<0.001), which was increased ~10-fold at both midand post-intervention versus baseline. No significant intervention effect was found for NK surface receptor expression, except for CXCR3 determined as mean fluorescence intensity (p=0.044, although with no significant differences in post hoc pairwise comparisons). The proteins showing a higher differential expression (Log2 fold-change > 10 and false discovery rate [FDR] q-value < 0.001) were COP9 signalosome subunit 3 (COPS3), DnaJ heat shock protein family member B11 (DNAJB11), histidyl-TRNA synthetase 1 (HARS), NIMA related kinase 9 (NEK9), nucleoporin 88 (NUP88), phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), regulator of chromosome condensation 2 (RCC2), TAO kinase 3 (TAOK3), transducin beta like 2 (TBL2), and ring finger protein 40 (RNF40). All were upregulated at mid-intervention compared with baseline, with the exception of HARS, which was downregulated. Four enriched pathways (FDR p<25%) were found: two related to transmembrane transport and cellular composition (downregulated at mid-intervention vs baseline), and two related to oxidation- reduction reactions (regulated at post-intervention versus baseline). A progressive exercise intervention of MICT followed by HIIT induces a remarkable improvement in NK function compared with the untrained state, although at the mechanistic level the pathways involved seem to differ over time during the intervention.

Ageing is associated with alterations in the immune system as well as with alterations of the circadian rhythm. Immune cells show rhythmicity in execution of their tasks. Chronic inflammation (inflammaging), which is observed in the elderly, is mitigated by lifelong exercise. The aimed this study was to determine the acute effect of a maximal exercise test on clock genes, regulatory proteins and cytokine expression, and evaluate the effect of lifelong exercise on the expression of clock genes in subpopulations of effector-memory (EM) CD4+ and CD8+T cells and the association of these processes with the inflammatory profile. Therefore, this study aimed to investigate the expression of clock genes in subpopulations of effector memory (EM) CD4+ and CD8+ T cells in master athletes and healthy controls and further associate them with systemic inflammatory responses to acute exercise. The study population comprised national and international master athletes (n = 18) involved in three sports (athletics, swimming and judo). The control group (n = 8) comprised untrained healthy volunteers who had not participated in any regular and competitive physical exercise in the past 20 years. Anthropometric measurements and blood samples were taken before (Pre), 10 min after (Post) and 1 h after (1 h Post) a maximal cycle ergometer test for the determination of maximum oxygen consumption (VO2 max). The subpopulations of EM CD4+ and CD8+ T cells were purified using fluorescenceactivated cell sorting. RNA extraction of clock genes (CLOCK, BMAL1, PER1, PER2, CRY1, CRY2, REV-ERBα, REV-ERBβ, RORa, RORb and RORc) in EM CD4+ and EM CD8+ T cells as well as regulatory proteins (IL-4, IFN-γ, Tbx21, PD-1, Ki67, NF-kB, p53 and p21) in EM CD4+ T cells was performed. The serum concentration of cytokines (IL-8, IL-10, IL-12p70 and IL-17A) was measured. The master athletes showed better physiological parameters than the untrained healthy controls (P < 0.05). The levels of cytokines increased in master athletes at Post compared with those at Pre. The IL-8 level was higher at 1 h Post, whereas the IL-10 and IL-12p70 levels returned to baseline. There was no change in IL-17A levels (P < 0.05). The clock genes were modulated differently in CD4+ T cells after an acute session of exercise in a training status-dependent manner. The synchronization of clock genes, immune function and ageing presents new dimensions with interesting challenges. Lifelong athletes showed modified expression patterns of clock genes and cytokine production associated with the physical fitness level. Moreover, the acute bout of exercise altered the clock machinery mainly in CD4+ T cells; however, the clock gene expressions induced by acute exercise were different between the master athletes and control group.

Numerous epidemiological studies have shown the existence of a relationship between exercise and reduced risk of different types of cancer. In vitro studies have identified a direct effect of exercise-conditioned human serum on cancer cell lines of the lung, breast, prostate, and colon. The aim of this systematic review with meta-analysis (SRM) was to estimate the magnitude of the effect that exercise-conditioned human serum produced on the viability of cancer cell cultures. The design followed the PRISMA guidelines and the TREND statement to assess the quality of information (QoI) in each study. Nine in vitro studies were included in the SRM, involving a total of nine cancer cell lines and serum from 244 individuals from different countries, including namely healthy sedentary individuals, at risk of prostate cancer individuals and cancer patients, with ages ranging from 18 to 73 years. The impact of exerciseconditioned human serum on the viability of cancer cell cultures was analysed by a variety of assays, using pre-exercise human serum for comparison purposes. Globally, cultures of cancer cell lines exposed to human serum conditioned by exercise of various intensities exhibited a reduced viability, when compared with control cultures, with an overall effect size of -1.126 (95% CI; -1.300 to -0.952; p < 0.001). When the analysis only included human serum conditioned by high intensity exercise, the effect became more pronounced (ES -1.350; -1.522 to -1.179 (95% CI); p < 0.001). These results are in line with the hypothesis that changes in human serum induced by exercise might play a role in the beneficial effects of physical activity in cancer prevention and management and that these effects depend on exercise intensity.

Individuals with amnestic mild cognitive impairment (aMCI) experience cognitive declines in learning and memory greater than expected for normal aging, and are at a high risk of dementia. We previously reported that sedentary aMCI patients exhibited neuroinflammation that correlated with brain amyloid beta (Aβ) burden, as determined by 18F-florbetapir positron emission tomography (PET). These aMCI patients enrolled in a one-year randomized control trial (AETMCI, NCT01146717) to test the beneficial effects of 12 months of moderate-to-high intensity aerobic exercise training (AET) or stretching/toning (ST) control intervention on neurocognitive function. A subset of aMCI participants had PET imaging, cognitive testing, and immunophenotyping of cerebrospinal fluid (CSF) and peripheral blood after AET or ST interventions. As adaptive immune responses were similar between AET and ST groups, we combined AET/ST into a general 'physical activity' (PA) group and compared Aβ burden, cognitive function, and adaptive immune cell subsets to sedentary lifestyle before intervention. We found that PAinduced immunomodulation of CD4+ and CD8+ T cells in CSF correlated with changes in Aβ burden in brain regions associated with executive function. Furthermore, after PA, cognitive scores on tests of memory, processing speed, attention, verbal fluency, and executive function were associated with increased percent representation of circulating naïve B + T cells. We review the literature on aMCI-related cognition and immune changes as they relate to exercise, and highlight how our preliminary data suggest a complex interplay between the adaptive immune system, physical activity, cognition, and Aβ burden in aMCI.

Multiple studies in humans and animals have demonstrated the profound impact that exercise can have on the immune system. There is a general consensus that regular bouts of short-lasting (i.e. up to 45 minutes) moderate intensity exercise is beneficial for host immune defense, particularly in older adults and people with chronic diseases. In contrast, infection burden is reported to be high among high performance athletes and second only to injury for the number of training days lost during preparation for major sporting events. This has shaped the common view that arduous exercise (i.e. those activities practiced by high performance athletes/ military personnel that greatly exceed recommended physical activity guidelines) can suppress immunity and increase infection risk. However, the idea that exercise per se can suppress immunity and increase infection risk independently of the many other factors (e.g. anxiety, sleep disruption, travel, exposure, nutritional deficits, environmental extremes, etc.) experienced by these populations has recently been challenged. The purpose of this debate article was to solicit opposing arguments centered around this fundamental question in the exercise immunology field: can exercise affect immune function to increase susceptibility to infection. Issues that were contested between the debating groups include: (i) whether or not athletes are more susceptible to infection (mainly of the upper respiratory tract) than the general population; (ii) whether exercise per se is capable of altering immunity to increase infection risk independently of the multiple factors that activate shared immune pathways and are unique to the study populations involved; (iii) the usefulness of certain biomarkers and the interpretation of in vitro and in vivo data to monitor immune health in those who perform arduous exercise; and (iv) the quality of scientific evidence that has been used to substantiate claims for and against the potential negative effects of arduous exercise on immunity and infection risk. A key point of agreement between the groups is that infection susceptibility has a multifactorial underpinning. An issue that remains to be resolved is whether exercise per se is a causative factor of increased infection risk in athletes. This article should provide impetus for more empirical research to unravel the complex questions that surround this contentious issue in the field of exercise immunology.