CD4 cytotoxic T lymphocytes (CD4 CTLs) in supercentenarians represent an intriguing immunological signature linked to healthy aging and a potentially enhanced ability to respond to age-related threats.
Supercentenarians, individuals who live to 110 years or more, provide a model of healthy aging, achieving remarkable longevity by avoiding or delaying the onset of major age-associated diseases such as cardiovascular disorders and cancer. They maintain immune, cardiovascular, and epigenomic profiles that appear younger than expected for their chronological age.
In supercentenarians, a high frequency of CD4 cytotoxic T lymphocytes (CD4 CTLs) has been observed within peripheral blood mononuclear cells (PBMCs). These CD4 CTLs typically display loss of CD27 and CD28, a feature commonly associated with highly differentiated CD4 and CD8 T cells in the context of aging.
CD4 CTLs: The State of the Art
CD4 CTLs are an unusual subset of T cells that express both CD4 and cytotoxic effector molecules, a trait that makes them an exception to the conventional CD4/CD8 lineage classification.
Under physiological conditions, CD4 CTLs are rare in peripheral blood, typically accounting for less than 5% of the total T cell population. By contrast, CD4 CTLs have been consistently detected in the context of viral infections such as CMV, HIV, and SARS-CoV-2: multiple studies have reported their antiviral activity through the secretion of perforin and granzymes and the activation of the Fas/FasL pathway.
Recent research has also shown that CD4 CTLs can kill tumor cells in a manner dependent on Major Histocompatibility Complex (MHC) class II across various cancer types, including non-small cell lung cancer (NSCLC), bladder cancer, melanoma, and colorectal cancer.
A Possible Role in Cancer Defense
The role of CD4 CTLs in the context of healthy aging remains unclear, particularly in individuals like supercentenarians who maintain good health with a high frequency of CD4 CTLs.
Using single-cell immune profiling, a recent study published in Cell Reports examined T cells from supercentenarians. The researchers evaluated 28 Japanese individuals, divided into three groups: eight aged 70–99, ten aged 100–109, and another ten aged at least 110.
“Rather than showing signs of exhaustion, the CD4 CTLs remain highly active and could help the body cope with persistent threats that rise with age,” said the study’s first author, Kosuke Hashimoto.
The study reported that CD4 CTLs begin to expand around age 100, with a sequential loss of CD27/CD28 without evidence of exhaustion. The CD4 CTLs were dominated by large clones, with the major clones representing on average 33.3%, indicating a repeated stimulation by persistent antigens.
In addition, the CDR3β sequences of the major clones matched those of tumor-expanded T cells, particularly in lung carcinoma. Ex vivo stimulation experiments revealed that CD4 CTLs comprise subpopulations defined by interleukin-expression patterns, suggesting plasticity within the same clone.
“The resemblance between these receptor sequences and those found in T cells isolated from tumors suggests that CD4 CTLs could help recognize tumors before they become clinically detectable,” added Hashimoto. “It may be that immune changes in extremely advanced age are better understood as a reorganization of the immune system rather than a simple weakening.”
In conclusion, the findings suggest that CD4 CTLs expand and diversify as an adaptation to persistent antigens, potentially contributing to longevity through tumor control.
Study
Kosuke Hashimoto, Miki Kojima-Ishiyama, Hajime Inokuchi et al. CD4 CTLs in supercentenarians: Signs of adaptive expansion in healthy aging, Cell Reports, 2026, 117728, ISSN 2211-1247, https://doi.org/10.1016/j.celrep.2026.117728
Abbonati a Karla Miller
