Epidemiological evidence indicates that regular physical activity and/or frequent structured exercise reduces the incidence of many chronic diseases in older age, including communicable diseases such as viral and bacterial infections, as well as non-communicable diseases such as cancer and chronic inflammatory disorders. Despite the apparent health benefits achieved by leading an active lifestyle, which imply that regular physical activity and frequent exercise enhance immune competency and regulation, the effect of a single bout of exercise on immune function remains a controversial topic. Indeed, to this day, it is perceived by many that a vigorous bout of exercise can temporarily suppress immune function. In the first part of this review, we deconstruct the key pillars which lay the foundation to this theory—referred to as the “open window” hypothesis—and highlight that: (i) limited reliable evidence exists to support the claim that vigorous exercise heightens risk of opportunistic infections; (ii) purported changes to mucosal immunity, namely salivary IgA levels, after exercise do not signpost a period of immune suppression; and (iii) the dramatic reductions to lymphocyte numbers and function 1–2 h after exercise reflects a transient and time-dependent redistribution of immune cells to peripheral tissues, resulting in a heightened state of immune surveillance and immune regulation, as opposed to immune suppression. In the second part of this review, we provide evidence that frequent exercise enhances—rather than suppresses—immune competency, and highlight key findings from human vaccination studies which show heightened responses to bacterial and viral antigens following bouts of exercise. Finally, in the third part of this review, we highlight that regular physical activity and frequent exercise might limit or delay aging of the immune system, providing further evidence that exercise is beneficial for immunological health. In summary, the over-arching aim of this review is to rebalance opinion over the perceived relationships between exercise and immune function. We emphasize that it is a misconception to label any form of acute exercise as immunosuppressive, and, instead, exercise most likely improves immune competency across the lifespan.

Deregulation of signaling pathways involving phosphorylation is a hallmark of malignant transformation. Degradation of phosphoproteins generates cancer-specific phosphopeptides that are associated with MHC-I and II molecules and recognized by T-cells. We identified 95 phosphopeptides presented on the surface of primary hematological tumors and normal tissues, including 61 that were tumor-specific. Phosphopeptides were more prevalent on more aggressive and malignant samples. CD8 T-cell lines specific for these phosphopeptides recognized and killed both leukemia cell lines and HLA-matched primary leukemia cells ex vivo. Healthy individuals showed surprisingly high levels of CD8 T-cell responses against many of these phosphopeptides within the circulating memory compartment. This immunity was significantly reduced or absent in some leukemia patients, which correlated with clinical outcome, and was restored following allogeneic stem cell transplantation. These results suggest that phosphopeptides may be targets of cancer immune surveillance in humans, and point to their importance for development of vaccine-based and T-cell adoptive transfer immunotherapies..

Purpose Epstein-Barr virus (EBV) is associated with several cancers in which the tumour cells express EBV antigens EBNA1 and LMP2. A therapeutic vaccine comprising a recombinant vaccinia virus, MVA-EL, was designed to boost immunity to these tumour antigens. A phase I trial was conducted to demonstrate the safety and immunogenicity of MVA-EL across a range of doses. Experimental Design Sixteen patients in the United Kingdom (UK) with EBV-positive nasopharyngeal carcinoma (NPC), received three intradermal vaccinations of MVA-EL at 3-weekly intervals at dose levels between 5×107 and 5×108 plaque forming units (pfu). Blood samples were taken at screening, after each vaccine cycle and during the post-vaccination period. T-cell responses were measured using IFNγ ELISpot assays with overlapping EBNA1/LMP2 peptide mixes or HLA-matched epitope peptides. Polychromatic flow cytometry was used to characterize functionally responsive T-cell populations. Results Vaccination was generally well-tolerated. Immunity increased after vaccination to at least one antigen in 8/14 patients (7/14, EBNA1; 6/14, LMP2), including recognition of epitopes that vary between EBV strains associated with different ethnic groups. Immunophenotypic analysis revealed that vaccination induced differentiation and functional diversification of responsive T-cell populations specific for EBNA1 and LMP2 within the CD4 and CD8 compartments respectively. Conclusions MVA-EL is safe and immunogenic across diverse ethnicities and thus suitable for use in trials against different EBV-positive cancers globally as well as in South East Asia where NPC is most common. The highest dose (5×108 pfu) is recommended for investigation in current phase IB and II trials.

Ageing, like obesity, is often associated with alterations in metabolic and inflammatory processes resulting in morbidity from diseases characterised by poor metabolic control, insulin insensitivity, and inflammation. Ageing populations also exhibit a decline in immune competence referred to as immunosenescence, which contributes to, or might be driven by chronic, low-grade inflammation termed “inflammageing”. In recent years, animal and human studies have started to uncover a role for immune cells within the stromal fraction of adipose tissue in driving the health complications that come with obesity, but relatively little work has been conducted in the context of immunometabolic adipose function in ageing. It is now clear that aberrant immune function within adipose tissue in obesity—including an accumulation of pro-inflammatory immune cell populations—plays a major role in the development of systemic chronic, low-grade inflammation, and limiting the function of adipocytes leading to an impaired fat handling capacity. As a consequence, these changes increase the chance of multiorgan dysfunction and disease onset. Considering the important role of the immune system in obesity-associated metabolic and inflammatory diseases, it is critically important to further understand the interplay between immunological processes and adipose tissue function, establishing whether this interaction contributes to age-associated immunometabolic dysfunction and inflammation. Therefore, the aim of this article is to summarise how the interaction between adipose tissue and the immune system changes with ageing, likely contributing to the age-associated increase in inflammatory activity and loss of metabolic control. To understand the potential mechanisms involved, parallels will be drawn to the current knowledge derived from investigations in obesity. We also highlight gaps in research and propose potential future directions based on the current evidence.

Oral squamous cell carcinoma (OSCC) is a lethal disease, with rising incidence. There were 6767 new OSCC cases and 2056 deaths in the UK in 2011. Cancers are preceded by oral potentially malignant disorders (PMDs), recognizable mucosal diseases harbouring increased SCC risk, offering clinicians a 'therapeutic window' to intervene. Contemporary practice remains unable to predict lesion behaviour or quantify malignant transformation risk. No clear management guidelines exist and it is unclear from the literature whether early diagnosis and intervention prevents cancer. Between 1996 and 2014, 773 laser treatments were performed on 590 PMD patients in Newcastle maxillofacial surgery departments. The efficacy of the intervention was examined by review of the clinicopathological details and clinical outcomes of the patients (mean follow-up 7.3 years). Histopathology required up-grading in 36.1% on examining excision specimens. Seventy-five percent of patients were disease-free, mostly younger patients with low-grade dysplasia; 9% exhibited persistent disease and were generally older with proliferative verrucous leukoplakia. Disease-free status was less likely for erythroleukoplakia (P=0.022), 'high-grade' dysplasia (P<0.0001), and with lichenoid inflammation (P=0.028). Unexpected OSCC was identified in 12.0%, whilst 4.8% transformed to malignancy. Interventional laser surgery facilitates definitive diagnosis and treatment, allows early diagnosis of OSCC, identifies progressive disease, and defines outcome categories. Evidence is lacking that intervention halts carcinogenesis. Multicentre, prospective, randomized controlled trials are needed to confirm the efficacy of surgery.

The adoption of regular structured exercise in previously sedentary, middle-aged, and overweight men does not result in a negative compensatory reduction in nonprescribed physical activity. The less-than-predicted weight loss is likely to reflect a compensatory increase in energy intake in response to a perceived state of relative energy insufficiency.

Regular exercise may improve systemic markers of chronic inflammation, but direct evidence and dose-response information is lacking. The objective of this study was to examine the effect and time course of changes in markers of chronic inflammation in response to progressive exercise training (and subsequent detraining). Forty-one sedentary men 45-64 yr of age completed either a progressive 24-wk exercise intervention or control followed by short-term removal of the intervention (2-wk detraining). Serum IL-6 fell by -0.4 pg/ml (SD 0.6) after 12 wk and responded to moderate-intensity exercise. Serum alanine aminotransferase (ALT) activity fell -7 U/l (SD 11) at 24 wk although there was no evidence of any change by week 12 (and therefore ALT required more vigorous-intensity activity and/or a more prolonged intervention). The effect on IL-6 was lost after 2-wk detraining whereas the change in ALT was retained. The temporal fall and rise in IL-6 with training and subsequent detraining in men with high IL-6 at baseline provided a retrospective opportunity to examine parallel genomic changes in peripheral mononuclear cells. A subset of 53 probes was differentially regulated by at least twofold after training with 31 of these changes being lost after detraining (n = 6). IL-6 responded quickly to the carefully monitored exercise intervention (within weeks) and required only moderate-intensity exercise, whereas ALT took longer to change and/or required more vigorous-intensity exercise. Further work is required to determine whether any of the genes that temporally changed in parallel with changes in IL-6 are a cause or consequence of this response.

Exercise induces mobilisation of CD8+ T lymphocytes (CD8TL) into the peripheral blood. This response is largely confined to effector-memory CD8TLs: antigen experienced cells which have a strong tissue-homing and effector potential. This study investigated whether effector-memory cells also account for the CD8TL egress from peripheral blood following exercise. As latent Cytomegalovirus (CMV) infection is associated with a robust expansion in the number and proportion of effector-memory CD8TLs, we also investigated if CMV serostatus was a determinant of the CD8TL responses to exercise. Fourteen males (Mean age 35, SD ± 14 yrs), half of whom were CMV seropositive (CMV+), ran on a treadmill for 60 min at 80% V_ O2 max. Blood was collected at baseline, during the final minute of exercise, and 15 min and 60 min thereafter. CD8TL memory subsets were characterised by flow cytometry, using the cell-surface markers CD45RA, CD27, and CD28. The results confirmed that CD8TLswith an effector-memory phenotype (CD27CD28CD45RA+/) exhibited the largest increase during exercise (+200% to +250%), and also showed the largest egress from blood 60 min post-exercise (down to 40% of baseline values). Strikingly, the mobilisation and subsequent egress of total CD8TLs was nearly twice as large in CMV+ individuals. This effect appeared specific to CD8TLs, and was not seen for CD4+ T lymphocytes or total lymphocytes. This effect of CMV serostatus was largely driven by the higher numbers of exercise-responsive effector-memory CD8TLs in the CMV+ participants. This is the first study to demonstrate that infection history is a determinant of immune system responses to exercise