Exercise enhances vaccine-induced antigen-specific T cell responses☆
Introduction
The favorable effects of a physically active lifestyle on a number of physiological processes, including cardiovascular function and insulin sensitivity, and the concomitant reduction in disease outcomes such as coronary heart disease, hypertension and diabetes are well documented [1], [2]. However, the effects of physical activity on immune function and the downstream consequences on disease risk have been studied to a lesser extent. The current hypothesis to explain the relationship between exercise and immune function is the Inverted J Hypothesis [3], which proposes that regular, moderate exercise enhances immune function, and in turn, may reduce the incidence of infectious disease and cancer. In contrast, physical inactivity and intense, exhaustive exercise at opposite ends of the curve both suppress immune function and may increase disease risk.
Although it has been proposed that moderate physical activity may provide protection from the incidence of infectious disease via an enhancement of immunity, few studies have addressed this question. Clinical and epidemiological studies demonstrate that the incidence of upper respiratory tract infections (URTI) [4], [5], [6], [7] and the severity of symptoms [8], [9], [10], [11], [12] are significantly lower in moderately active individuals as compared to their sedentary counterparts. In animal studies, the survival rates following infection with Salmonella typhimurium[13] or influenza virus [14] are higher in active mice as compared to sedentary controls. However, immune function was measured in only two of the studies in which the incidence and severity of symptoms of URTI were reduced with moderate activity [6], [12]. Both studies demonstrate an increase in the mucosal antibody response (i.e. salivary IgA concentration) in moderately active individuals [6], [12]. Several other studies report an elevation in mucosal IgA in moderately active young [15], [16] and older adults [17] but did not measure URTI or other clinical endpoints. Finally, we have demonstrated that moderate exercise enhances mucosal T cell proliferation and cytokine production in response to concanavalin A (Con A) stimulation in mice [18]. The limited work in this area suggests that moderate exercise enhances antigen independent measures of immune function, e.g. total IgA and mitogen-induced T cell responses. However, no studies have examined the effect of moderate exercise on antigen-specific mucosal immunity in response to vaccination.
In addition to examining broad-based, mucosal immune endpoints, numerous studies have demonstrated a beneficial effect of moderate exercise on systemic innate immunity, in particular the phagocytic and tumoricidal activities of macrophages and the cytotoxicity of NK cells (reviewed in Refs. [19], [20]). A few studies have examined the effect of regular moderate exercise on systemic adaptive immune responses, but in most cases, in the context of an aging model. Several cross-sectional studies demonstrate that active older adults have higher antigen-specific antibody titers [21], [22], [23], higher influenza-specific in vitro peripheral blood mononuclear cell proliferation [22] and greater in vivo delayed type hypersensitivity (DTH) responses [23] as compared to sedentary individuals. Furthermore, two prospective studies in older adults reported that a 10-month exercise intervention increased influenza- and keyhole-limpet hemocyanin (KLH)-specific antibody titers [24], [25] and granzyme B activity [25]. In contrast to the exercise-induced enhancement of antigen-specific antibody titers in older adults, moderate exercise does not enhance antibody responses in young adults [23], [26], [27] or in rodent models utilizing young animals [23], [28], [29], [30], [31]. However, one report demonstrates that DTH responses to KLH are higher in active versus sedentary young adults [23]. The studies that have been done in young animals suggest that moderate exercise may enhance cell-mediated but not humoral responses; however, additional well-designed mechanistic studies are needed to further characterize the effects of moderate activity on adaptive immune responses.
Therefore, the goals of the present study were (1) to establish a reliable model to systematically evaluate the effects of moderate physical activity on adaptive immune responses to vaccination, (2) to characterize the effect of moderate exercise on humoral and cell-mediated immune responses in the mucosal compartment using a vaccine platform that is well-documented to stimulate mucosal immunity [32] and (3) to explore the effect of the same vaccine platform on systemic immunity in an effort to compare and contrast the effect of exercise on adaptive immunity in both compartments.
Section snippets
Animals and treatment regimens
Female 6-week-old C57BL/6 mice were obtained from Charles River Breeding Laboratory (Frederick, MD). Animal care was provided in accordance with the procedures outlined in the “Guide for the Care and Use of Laboratory Animals.” Upon receipt, mice were screened for voluntary running behavior by being placed into individual cages fitted with a mouse running wheel apparatus (MiniMitter Co.; Bend, OR) for 4 days to determine the average level of running activity per mouse. Wheel revolutions of
Establishment of a reliable model of moderate voluntary running in mice
Previous studies in our laboratory demonstrated that running behavior is heterogeneous in C57BL/6 mice given access to voluntary running wheels [18]. Thus, to study the effects of moderate voluntary exercise on immune function we selected animals that would choose to run over the course of the 12-week experiment. In a pilot study, we compared the average running activity of mice (km/day) after 1, 4, 10, and 14 days of access to running wheels to the average distance/day run over 6 weeks. We
Discussion
To our knowledge, this study is the first to evaluate the effects of moderate exercise on antigen specific mucosal immunity in response to vaccination, and the first to compare and contrast the effect of moderate exercise on antigen specific immune responses in mucosal and systemic compartments. Furthermore, we evaluated both humoral and cell-mediated immune responses to vaccination in young, healthy animals. We have demonstrated that by selecting mice that voluntarily choose to run, all mice
Acknowledgements
We are grateful for the technical assistance of Garland Davis, Eileen Thompson, and Bertina Gibbs. The authors thank Debra Weingarten for her assistance in the preparation of this manuscript.
Conflict of interest: None.
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This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by the National Cancer Institute Cancer Prevention Fellowship Program. This work was also supported by funding to S. Hursting from NIEHS # P30 ES007784 and the Breast Cancer Research Foundation.