Ph.D. Candidate University of Texas at Arlington Arlington, Texas, United States
Disclosure(s):
Sogol Zahedi: No financial relationships to disclose
Introduction/Rationale: Aging profoundly reshapes the immune system, leading to impaired pathogen defense, increased cancer incidence, and chronic inflammation that drives tissue dysfunction. Among immune cells, T lymphocytes undergo one of the most pronounced age-related shifts, losing naïve populations and accumulating cytokine-producing memory cells. EOMES is a transcription factor essential for effector and virtual memory CD8⁺ T-cell differentiation and cytotoxic activity. EOMES⁺ T cells accumulate with age and contribute to tissue inflammation through sustained production of IFN-γ and other inflammatory mediators. While these cells may exacerbate sterile inflammation, their role in maintaining tumor immunosurveillance during aging remains poorly defined. To determine how EOMES⁺ T cells contribute to age-related inflammation and tissue dysfunction, we generated T-cell–specific Eomes knockout mice (CD8a-Cre; Eomes fl/fl) and aged them alongside wild-type littermates.
Methods: Lifespan, organ pathology, and immune phenotypes were assessed by necropsy, histology, flow cytometry, and multiplex immunohistochemistry for CD3, CD20, and Iba1.
Results: Contrary to our hypothesis that EOMES deletion would preserve a youthful T-cell profile, by 15 months of age 50% of Eomes-deficient mice had died compared with ~15% of controls, and by 18 months survival was ~25% versus ~65%, respectively (P < 0.0001). Knockout mice also developed multifocal neoplasms absent in controls. Immunopathology revealed admixed Iba1⁺ macrophages and CD20⁺ B cells with minimal CD3⁺ T-cell neoplasia, consistent with histiocyte-rich B-cell lymphoma.
Conclusion: These findings demonstrate that loss of EOMES-dependent cytotoxic surveillance permits malignant transformation. We propose that although EOMES-dependent immunosurveillance is critical for tumor suppression, its persistent activation with age may also contribute to age-related chronic inflammation, possibly linking antitumor immunity to inflammaging.
