Neonatal CD4⁺ T cells have a characteristic transcriptome and epigenome and respond to TCR stimulation with proliferation and yet a limited immune response

The adaptive immune response is coordinated by CD4(+) T cells, which determine the type and strength of the immune response and the effector cells involved. It has been reported that CD4(+) T cells are less responsive in neonates, leading to low activation of the cellular response and poor antibody production by B cells. This low response is essential for the tolerant window that favors birth transition from the sterile environment in the womb to the outside world but leaves neonates vulnerable to infection, which is still an important health issue. Neonates have a high morbidity and mortality rate due to infections, and the molecular reasons are still understudied. We asked whether the neonatal naive CD4(+) T cells have a genomic program that predisposes them to a low response. Therefore, we evaluated the transcriptome and epigenome of human neonatal and adult naive CD4(+) T cells. Our results point to a gene expression profile forming a distinct regulatory network in neonatal cells, which favors proliferation and a low T-cell response. Such expression profile is supported by a characteristic epigenetic landscape of neonatal CD4(+) T cells, which correlates with the characteristic transcriptome of the neonatal cells. These results were confirmed by experiments showing a low response to activation signals, higher proliferation, and lower expression of cytokines of neonatal CD4(+) T cells as compared to adult cells. Understanding this network could lead to novel vaccine formulations and better deal with life-threatening diseases during this highly vulnerable period of our lives.