CD4 CTLs in supercentenarians: Signs of adaptive expansion in healthy aging

Hashimoto K, Kojima-Ishiyama M, Inokuchi H et al. Cell Reports, 2026; 0

Highlights

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CD4 CTLs expand around age 100 without signs of exhaustion

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A CD27−CD28+ state marks the intermediate helper-to-killer transition

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Large private CD4 CTL clones suggest repeated antigen exposure

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Single clones diversify cytokine profiles after ex vivo stimulation

Summary

Graphical Abstract

Our previous study identified CD4 cytotoxic T lymphocytes (CD4 CTLs) as a hallmark of supercentenarians. CD4 CTLs have primarily been studied in disease contexts; however, their role in healthy aging remains unclear. Using single-cell immune profiling, we analyzed T cells from supercentenarians and found that CD4 CTLs begin to expand around the age of 100, characterized by sequential CD27/CD28 loss without exhaustion. CD4 CTLs were dominated by large clones, with top clones averaging 33.3%, indicating repeated stimulation by persistent antigens. Furthermore, CDR3β sequences of the top clones matched those of T cells expanded in tumors, particularly lung cancer. Ex vivo stimulation experiments revealed that CD4 CTLs consist of subgroups defined by interleukin expression patterns, suggesting their plasticity within the same clone. These findings suggest that CD4 CTLs expand and diversify as an adaptation to persistent antigens, potentially contributing to longevity through cancer suppression.

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