PMC

Distribution of EM and EMRA in CD4+ T-cells into subsets defined by CD28 and CD27 expression. (A) Schematic model of the EM and EMRA CD4+ T-cells differentiation subsets accordingly to CD27 and CD28 expression. EM T-cells can be divided into EM1 (CD27 + CD28 +), EM2 (CD27 + CD28^null, only in CD8 +  T-cells), EM3 (CD27^nullCD28^null), and EM4 (CD27^nullCD28 +). Similarly, EMRA can be divided into pE1 (CD27 + CD28+) and pE2 (CD27 + CD28^null, only in CD8 T-cells) and E (CD27^nullCD28^null). (B) Dot-plots representatives of the EM and EMRA subsets in young people and elderly subjects into the CD4+ T-cells.

Distribution of CD4+ T-cells into naïve, central memory, effector memory (EM), and effector memory RA (EMRA). (A) Schematic model of the T-cells differentiation subsets accordingly to CD4 + 5RA and CCR7 expression. (B) Dot-plots representatives of the naïve, CM, EM, and EMRA subsets in young people and elderly subjects into the CD4+ T-cells. Whole blood was stained with anti-CD45RA-FICT, anti-CD8-PE, anti-CD4-PerCP, and anti-CCR7-APC, and 10⁵ cells were acquired in each experiment.

Effect of IL-15 homeostatic cytokine on CD4+ T-cells. (A) It is widely accepted that IL-7 signaling through the IL-7 receptor is essential for prolonged survival of naïve and memory T-cells. Naïve T-cells rely on survival signals through contact with self-peptide-loaded major histocompatibility complex (MHC) molecules plus interleukin IL-7. (B) Antigen-experienced (memory) T-cells are typically MHC-independent. They survive and undergo periodic homeostatic proliferation through contact with both IL-7 and IL-15. (C) IL-15 promotes the proliferation of late-memory CD4+ T-cells and enhances the proliferative response of CD28^null cells with respect to CD28+ CD4+ T-cells. IL-15 increases the cytolytic properties of CD4 + CD28^null T-cells and enhances their antigen-specific responses.

Older people present a different receptor repertoire from that of young individuals. Despite the decline of thymic function and the low TCR diversity, the elderly CD4+ T-cells present novel functions attributed to their acquisition of NK-related receptors (NKRs) such as KIR, CD94, CD16, CD56, NKG2, and KLRG1. CD4+ T-cells undergo senescence due to lifetime exposure to persistent pathogens and to homeostatic proliferation. With advancing age, the T-cell repertoire becomes populated with highly oligoclonal, long-lived T-cells, most of which have lost the ability to express CD28. Such CD28^null T-cells have limited proliferative capacity, but are functionally active. They are generally long-lived and functionally active.