The human immune system has specialized cells called CD4 cytotoxic T lymphocytes (CD4 CTLs), which have been shown to kill tumor cells in some cancers. These cells multiply in a process called clonal expansion to help fight infection. In a study published by Hashimoto in Cell Reports, researchers showed that these immune cells also may play a role in healthy aging among supercentenarians—individuals who live to or beyond 110 years.
“Immune aging is not simply a process of decline,” explained first author Kosuke Hashimoto, PhD, an Associate Professor at the University of Osaka in Japan. “The selective expansion of certain T cells suggests that, even in extreme old age, the immune system may continue to adapt to age-related challenges.”
CD4 CTLs are a cellular signature of supercentenarians. In this study, researchers discovered that these cells expand and adapt within this older population.
“CD4 CTLs are an atypical and relatively rare T-cell population,” Dr. Hashimoto said. “Their marked increase in supercentenarians may provide important clues as to how the immune system is maintained in extreme old age.”
The researchers analyzed the blood samples of 28 adults who had been divided into three age groups: 70–99 years, 100–109 years, and 110 years and older. The proportion of CD4 CTLs increased with age, with median percentages of 4%, 9.6%, and 17.6%, respectively.
While the results suggest CD4 CTL expansion begins around age 100, this phenomenon was not unique to centenarians and supercentenarians; one participant younger than 100 had the highest proportion of these cells.
The team then looked at participants’ T-cell receptors and determined that clonal expansion helps drive this increase. CD4 CTLs clone themselves when the immune system is under attack. In the study, the most prominent clone accounted for an average 33.3% of CD4 CTLs, indicating that older adults may be responding to persistent immune threats. In one centenarian’s blood sample, a single clone accounted for 53.8% of their CD4 CTLs.
Next, the researchers matched the receptor sequences of each participant’s top CD4 CTL clone to those in a public database. Nearly three dozen matches belonged to people with cancer—namely lung, breast, and liver cancers. Because none of the centenarians or supercentenarians studied had been diagnosed with these cancers, the researchers theorized that their CD4 CTL expansion may reflect early immune responses.
“Some CD4 CTLs may recognize cancer-related targets, although their exact targets remain unknown,” Dr. Hashimoto said.
The study, which focused on T cells circulating in the blood, does not prove that having an abundance of CD4 CTLs prevents cancer or causes a person to live longer. Dr. Hashimoto said the team’s next step is to research how these cells behave in human tissues.
“As we age, abnormal cells, including senescent and cancerous cells, become more common,” Dr. Hashimoto noted. “Our findings suggest that immune adaptation to these changes may contribute to exceptional longevity.”
DISCLOSURE: This work was supported by Japan Society for the Promotion of Science KAKENHI grants; the Promotion Program for Frontier Protein Research from the Institute for Protein Research; the University of Osaka; the Takeda Science Foundation; the Mochida Memorial Foundation for Medical and Pharmaceutical Research; research grants for Keio University Global Initiative Research Projects; and a research grant from the Ministry of Education, Culture, Sports, Science and Technology to the RIKEN Center for Integrative Medical Sciences. For full disclosures of the study authors, visit cell.com/cell-reports.
