title: Environmental enrichment alters splenic immune cell composition and enhances secondary influenza vaccine responses in mice.
abstract: Chronic stress has deleterious effects on immune function, which can lead to adverse health outcomes. However, studies investigating the impact of stress reduction interventions on immunity in clinical research have yielded divergent results, potentially stemming from differences in study design and genetic heterogeneity, among other clinical research challenges. To test the hypothesis that reducing glucocorticoid levels enhances certain immune functions, we administered influenza vaccine once (prime) or twice (boost) to mice housed in either standard control caging or environmental enrichment (EE) caging. We have shown that this approach reduces mouse corticosterone production. Compared with controls, EE mice had significantly lower levels of fecal corticosterone metabolites (FCMs) and increased splenic B and T lymphocyte numbers. Corticosterone levels were negatively associated with the numbers of CD19(+) (r(2) = 0.43, p = 0.0017), CD4(+) (r(2) = 0.28, p = 0.0154) and CD8(+) cells (r(2) = 0.20, p = 0.0503). Vaccinated mice showed nonsignificant differences in immunoglobulin G (IgG) titer between caging groups, although EE mice tended to exhibit larger increases in titer from prime to boost than controls; the interaction between the caging group (control versus EE) and vaccine group (prime versus boost) showed a strong statistical trend (cage-group*vaccine-group, F = 4.27, p = 0.0555), suggesting that there may be distinct effects of EE caging on primary versus secondary IgG vaccine responses. Vaccine-stimulated splenocytes from boosted EE mice had a significantly greater frequency of interleukin 5 (IL-5)-secreting cells than boosted controls (mean difference 7.7, IL-5 spot-forming units/10(6) splenocytes, 95% confidence interval 0.24-135.1, p = 0.0493) and showed a greater increase in the frequency of IL-5-secreting cells from prime to boost. Our results suggest that corticosterone reduction via EE caging was associated with enhanced secondary vaccine responses, but had little effect on primary responses in mice. These findings help identify differences in primary and secondary vaccine responses in relationship to stress mediators that may be relevant in clinical studies.
authors.affiliation: Osher Center for Integrative Medicine, University of California, San Francisco, California, United States of America Division of Experimental Medicine, University of California, San Francisco, California, United States of America.
authors.forename: Blake T
authors.initials: BT
authors.lastname: Gurfein
authors.affiliation: Chaire ANCA, Food Science, Nutrition and Eating Behavior, AgroParisTech, Paris, France INRA, Unit 914 Nutrition Physiology and Ingestive Behavior, AgroParisTech, Paris, France.
authors.forename: Olga
authors.initials: O
authors.lastname: Davidenko
authors.affiliation: Division of Experimental Medicine, University of California, San Francisco, California, United States of America.
authors.forename: Mary
authors.initials: M
authors.lastname: Premenko-Lanier
authors.affiliation: Division of Experimental Medicine, University of California, San Francisco, California, United States of America.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Milush
authors.affiliation: Osher Center for Integrative Medicine, University of California, San Francisco, California, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Acree
authors.affiliation: Department of Physiology, University of California, San Francisco, California, United States of America.
authors.forename: Mary F
authors.initials: MF
authors.lastname: Dallman
authors.affiliation: Research Group of Psychoneuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Chadi
authors.initials: C
authors.lastname: Touma
authors.affiliation: Department of Biomedical Sciences/Biochemistry, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Rupert
authors.initials: R
authors.lastname: Palme
authors.affiliation: Division of Experimental Medicine, University of California, San Francisco, California, United States of America.
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: York
authors.affiliation: INRA, Unit 914 Nutrition Physiology and Ingestive Behavior, AgroParisTech, Paris, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Fromentin
authors.affiliation: Chaire ANCA, Food Science, Nutrition and Eating Behavior, AgroParisTech, Paris, France INRA, Unit 914 Nutrition Physiology and Ingestive Behavior, AgroParisTech, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Darcel
authors.affiliation: Division of Experimental Medicine, University of California, San Francisco, California, United States of America.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Nixon
authors.affiliation: Osher Center for Integrative Medicine, University of California, San Francisco, California, United States of America.
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Hecht
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D003345:Corticosterone / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004780:Environment, Controlled; D007117:Immunization, Secondary; D007252:Influenza Vaccines / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D016207:Cytokines; D007252:Influenza Vaccines; D003345:Corticosterone