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Early effector CD8+ T-cell differentiation and function are supported by the PI3K-Akt-mTOR pathway, while the differentiation of late exhausted CD8+ T cells remains incompletely understood. We first characterized the metabolic heterogeneity of the progenitor, effector, and exhausted CD8+ T-cell subsets in chronic infection by utilizing the Compass algorithm, which provides metabolic state predictions based on single-cell RNA sequencing data and flux-based analysis. Our analysis revealed metabolic programs distinct to each subset of virus-specific CD8+ T cells. In addition, it is known that the differentiation of progenitor to effector CD8+ T cells depends on IL-21\u2013producing CD4+ T cells. We found that PIM1 kinase, a known regulator of cellular energy metabolism that functions downstream of IL-21 signaling, displays high gene expression in the effector CD8 T-cell subset. Using the lymphocytic choriomeningitis virus clone 13 model of chronic viral infection, we showed that CD8+ T cell\u2013specific deletion of PIM1 kinase impairs the differentiation and cytolytic function of late effector CD8+ T cells. Furthermore, deficiency in PIM1 kinase reduced oxidative and glycolytic metabolism, potentially contributing to the diminished effector differentiation and function. Overall, these data reveal not only the metabolic heterogeneity of exhausted CD8+ T cells, but also how metabolic regulation through the IL-21\u2013PIM1 axis impacts CD8+ T-cell differentiation.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag062","type":"journal-article","created":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T19:04:14Z","timestamp":1776625454000},"source":"Crossref","is-referenced-by-count":0,"title":["PIM1 kinase\u2013regulated cellular metabolism sustains differentiation and function of effector CD8+ T cells during chronic viral infection"],"prefix":"10.1093","volume":"215","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1320-9327","authenticated-orcid":false,"given":"Ashley K","family":"Brown","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin , Milwaukee, WI,","place":["United States"]},{"name":"Department of Pathology, Feinberg School of Medicine, Northwestern University , Chicago, IL,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongshen","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Feinberg School of Medicine, Northwestern University , Chicago, IL,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Feinberg School of Medicine, Northwestern University , Chicago, IL,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Feinberg School of Medicine, Northwestern University , Chicago, IL,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro A S","family":"Vaz de Castro","sequence":"additional","affiliation":[{"name":"Department of Pathology, Feinberg School of Medicine, Northwestern University , Chicago, IL,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moujtaba Y","family":"Kasmani","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin , Milwaukee, WI,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siying","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin , Milwaukee, WI,","place":["United States"]},{"name":"Department of Pathology, Feinberg School of Medicine, Northwestern University , Chicago, IL,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paytsar","family":"Topchyan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin , Milwaukee, WI,","place":["United 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