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Supercentenarians Have Increased Levels of Cytotoxic CD4 T Cells

NEW YORK – People who are especially long-lived have an increased number of cytotoxic CD4 T cells circulating in their blood, a new single-cell transcriptomic analysis has found.

Researchers have been studying supercentenarians — people who have reached 110 years of age or more — to better understand healthy aging. Many supercentenarians reach these old ages in good health, suggesting their immune systems might better protect them from disease.

Investigators in Japan, led by Piero Carninci at the Riken Center for Integrative Medicine, have now conducted a single-cell transcriptomic analysis of peripheral blood mononuclear cells from supercentenarians and controls. As they reported in the Proceedings of the National Academy of Sciences this week, they found that supercentenarians had an increased number of cytotoxic CD4 T cells, a type of cell that is typically not cytotoxic but a helper cell.

"The conversion of helper CD4 T cells to a cytotoxic variety might be an adaptation to the late stage of aging," the researchers wrote in their paper.

Using a droplet-based, single-cell RNA sequencing approach, they profiled peripheral blood mononuclear cells from seven supercentenarians and five controls between 50 and 80 years of age. Within these samples, they uncovered 10 distinct clusters representing different cell types, including B cells and T cells.

Supercentenarians, they found, tended to have a smaller proportion of B cells compared to controls. B cells made up about 2 percent of the immune cells in supercentenarian samples, while they made up 11 percent of immune cells from controls, a finding they confirmed through fluorescence-activated cell sorting analysis.

Though the T cell fraction of immune cells was largely similar between supercentenarians and controls — about 40 percent — the types of T cells in that fraction differed between the groups.

Supercentenarians' T cell contribution contained many more cytotoxic T cells than controls. Cytotoxic T cells made up about 80 percent of the T cell fraction in some supercentenarian individuals, while in controls, they comprised about 10 to 20 percent of the T cell fraction.

In particular, the researchers reported that the cytotoxic T cells within supercentenarians included a higher level of CD4 cytotoxic T cells (CTLs) — even though CD4+ T cells are usually non-cytotoxic helper T cells — and a higher level of CD8 cytotoxic T cells, as compared to controls. The level of γδ T cells in supercentenarians, though, was similar to controls. They also confirmed these findings through FACS analysis.

CD4 CTLs had transcriptomic profiles that resembled those of CD8 CTLs, the researchers noted. In particular, CD4 CTLs had increased expression of GZMA, GZMB, GZMH, PRF1, and NKG7 and decreased expression of CCR7, CD27, CD28, and IL7R. This indicated that CD4 CTLs make use of the transcriptional program of cytotoxic CD8 CTLs, while maintaining their CD4 expression.

As helper cells, CD4+ T cells generally regulate immune responses via cytokines, and the researchers found CD4 CTLs from supercentenarians could produce IFN-γ and TNF-α upon ex vivo stimulation. This, they said, suggests CD4 CTLs might boost immunosurveillance and the identification of emerging tumor cells or viral infections and keep supercentenarians healthy for longer.

"Our study reveals that supercentenarians have unique characteristics in their circulating lymphocytes, which may represent an essential adaptation to achieve exceptional longevity by sustaining immune responses to infections and diseases," the researchers wrote in their paper.

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