Helios expression in naive CD4+ T cells decreases from neonates to older adults.

Fetuses, neonates, and infants are vulnerable to infectious diseases. At the same time, they are exposed to many harmless antigens; therefore, suppressing unnecessary immune responses to maintain immune tolerance is a rational strategy. In the elderly, chronic inflammatory and autoimmune diseases are more likely to occur due to inappropriate and dysregulated immune responses. Helios, encoded by the IKZF2 gene, is a marker for natural regulatory T cells (Treg) but is also expressed at low levels in naive CD4+ T cells. Its expression decreases with age, which may contribute to an excessive immune response in older individuals. Flow cytometry and western blotting revealed that the decline in Helios expression begins in the early neonatal period and persists across subsequent life stages. Quantitative PCR showed that IKZF2 expression was significantly and strongly negatively correlated with age (decreased by 40% per decade). Integration of DNA methylation array data and public datasets identified significant age-associated epigenetic modifications within the IKZF2 gene body, which may partially explain the age-related reduction in its expression. Notably, these changes reflect a transition of naive CD4+ T cell characteristics: shifting from a "Treg-like" signature in neonates and infants-likely an adaptation to the extrauterine environment-toward a "memory-like" profile in older adults. In summary, Helios expression in human naive CD4+ T cells exhibits a continuous decline from the fetal stage through the neonatal, infant, childhood, adult, and elderly stages. This phenomenon may contribute to the shift from immune tolerance to immune response dominance over the course of aging.