{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T01:25:14Z","timestamp":1788830714895,"version":"build-2803163510"},"reference-count":535,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T00:00:00Z","timestamp":1757376000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Homeostasis must be maintained for the healthy living of an organism. In addition to physiological and anatomical homeostasis, the maintenance of the immune system, called immune homeostasis or immunohomeostasis, is critical for overall well-being and general homeostasis. CD8+ cytotoxic T cells\/lymphocytes (CTLs) are crucial components of the adaptive immune systems of all vertebrates with a thymus. Hence, the thymus is an essential primary lymphoid organ (PLO) for developing T cell-mediated immunity (TCMI) that comprises CD4+ helper T cells (Th) cells and their subtypes, such as Th0 (na\u00efve helper T cells), Th1 (pro-inflammatory Th cells that secrete IFN-\u03b3), Th2 (secrete type 2 cytokines, such as IL-4, IL-5, IL-6, IL-10, and IL-13), Th9 (secrete IL-9), Th17 (secrete IL-17), Th22 (secrete IL-22), follicular Th cells (Tfhs, secrete IL-21), regulatory T cells (Tregs), and CD8+CTLs. The current article explores the critical role of CD8+CTLs in the maintenance of immune homeostasis. The role of the thymus (PLO) in generating and regulating CD8+CTLs, as well as mobilizing them to distant lymph nodes (LNs) and the spleen, which are referred to as secondary lymphoid organs (SLOs) and target organs, is discussed in section two of the article. The subsequent third section discusses the role of CD8+CTLs\u2019 cytotoxic and immunoregulatory action to maintain immune homeostasis during infection and other inflammatory conditions. Moreover, they mask themselves to different cell types, like Th cells, such as Tc2s, Tc9s, Tc17s, and Tc22s, to maintain immune homeostasis. CD8+CTLs also behave as Tregs to exert their immunoregulatory functions. In addition to conventional CD8+CTLs, granzyme K (GzmK)+CD8+CTLs and CD4+CTLs with their cytotoxic action to maintain immune homeostasis have also been discussed. The next section discusses cell\u2013cell (APC\u2013CD8+CTL) interactions that not only increase the cytotoxic functions of CD8+CTLs but also program APCs to support their cytotoxic functions. These CD8+CTLs secrete different cytokines (IFN-\u03b3 and IL-10) and cytotoxic molecules (perforin and Gzms), which exert immunoregulatory actions to maintain immune homeostasis. The article concludes with a future perspective and a conclusion section, highlighting the critical need to understand CD8+CTLs\u2019 cytotoxic and immunoregulatory functions in maintaining immune homeostasis across various diseases, including those with newly identified roles for CD8+CTLs.<\/jats:p>","DOI":"10.3390\/ijms26188788","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T10:27:12Z","timestamp":1757500032000},"page":"8788","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Cytotoxic T Cells: Kill, Memorize, and Mask to Maintain Immune Homeostasis"],"prefix":"10.3390","volume":"26","author":[{"given":"Vijay","family":"Kumar","sequence":"first","affiliation":[{"name":"Laboratory of Tumor Immunology and Immunotherapy, Department of Surgery, Morehouse School of Medicine, Atlanta, GA 30310, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-1-0716-3754-8_1","article-title":"Immune Homeostasis: A Novel Example of Teamwork","volume":"2782","author":"Kumar","year":"2024","journal-title":"Methods Mol. 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