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Because high elevations generally have fewer and less virulent pathogens, movement from low to high elevations may result in changes to immunological selection pressures. However, the extent to which changes in immune exposure have interacted with organismal adaptation to high elevations is not well characterized. We used North American deer mice (Peromyscus maniculatus) to investigate whether adaptation to high elevations has modified immunity using a conventional immune challenge (lipopolysaccharide (LPS) injection). Highland-ancestry mice displayed a reduced and more variable fever as well as elevated circulating levels of corticosterone, a context-dependent fever suppressor. In addition, nearly 400 genes were differentially expressed in the spleen by both ancestry and LPS injection. These differences are indicative of broader ancestry-dependent differentiation in the physiological immune response. Our results demonstrate that adaptation to high-elevation environments can be coincident with changes to immune system function. As climate change allows pathogens to expand into high-elevation environments, differential immunity in locally adapted populations may have important consequences for disease impact and movement.<\/jats:p>","DOI":"10.1098\/rspb.2025.3292","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:09:27Z","timestamp":1777421367000},"source":"Crossref","is-referenced-by-count":0,"title":["High-elevation adaptation is associated with functional changes in the immune response of deer mice"],"prefix":"10.1098","volume":"293","author":[{"given":"Chloe E.","family":"Butler","sequence":"first","affiliation":[{"name":"Colorado State University 1 , , ,","place":["Fort Collins, CO, USA"],"department":["Department of Biology"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan J.","family":"Hemmerlein","sequence":"additional","affiliation":[{"name":"Colorado State University 1 , , ,","place":["Fort Collins, CO, USA"],"department":["Department of Biology"]},{"name":"Colorado State University 2 , , ,","place":["Fort Collins, CO, USA"],"department":["Cellular and Molecular Biology Graduate Program"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine","family":"Kiel","sequence":"additional","affiliation":[{"name":"Colorado State University 1 , , ,","place":["Fort Collins, CO, USA"],"department":["Department of Biology"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7262-9754","authenticated-orcid":false,"given":"Kathryn","family":"Wilsterman","sequence":"additional","affiliation":[{"name":"Colorado State University 1 , , ,","place":["Fort Collins, CO, USA"],"department":["Department of Biology"]},{"name":"Colorado State University 2 , , ,","place":["Fort Collins, CO, USA"],"department":["Cellular and Molecular Biology Graduate Program"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"175","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"2026042820092098100_R1","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1007\/978-3-319-76768-0_26","volume-title":"Advances in comparative immunology","author":"Schoenle","year":"2018"},{"key":"2026042820092098100_R2","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/j.1365-2435.2010.01777.x","article-title":"Fitness consequences of immune responses: strengthening the empirical framework for ecoimmunology","volume":"25","author":"Graham","year":"2011","journal-title":"Funct. 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