When Aging Reaches CD4+ T-Cells: Phenotypic and Functional Changes

Marco Antonio Moro-García, Rebeca Alonso-Arias, Carlos López-Larrea, Marco Antonio Moro-García, Rebeca Alonso-Arias, Carlos López-Larrea

Abstract

Beyond midlife, the immune system shows aging features and its defensive capability becomes impaired, by a process known as immunosenescence that involves many changes in the innate and adaptive responses. Innate immunity seems to be better preserved globally, while the adaptive immune response exhibits profound age-dependent modifications. Elderly people display a decline in numbers of naïve T-cells in peripheral blood and lymphoid tissues, while, in contrast, their proportion of highly differentiated effector and memory T-cells, such as the CD28(null) T-cells, increases markedly. Naïve and memory CD4+ T-cells constitute a highly dynamic system with constant homeostatic and antigen-driven proliferation, influx, and loss of T-cells. Thymic activity dwindles with age and essentially ceases in the later decades of life, severely constraining the generation of new T-cells. Homeostatic control mechanisms are very effective at maintaining a large and diverse subset of naïve CD4+ T-cells throughout life, but although later than in CD8 + T-cell compartment, these mechanisms ultimately fail with age.

Keywords: CMV; IL-15; NKRs; T-cells; immunosenescence; inflammation.

Figures

Figure 1
Figure 1
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.
Figure 2
Figure 2
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 + CD28null, only in CD8 +  T-cells), EM3 (CD27nullCD28null), and EM4 (CD27nullCD28 +). Similarly, EMRA can be divided into pE1 (CD27 + CD28+) and pE2 (CD27 + CD28null, only in CD8 T-cells) and E (CD27nullCD28null). (B) Dot-plots representatives of the EM and EMRA subsets in young people and elderly subjects into the CD4+ T-cells.
Figure 3
Figure 3
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 CD28null T-cells have limited proliferative capacity, but are functionally active. They are generally long-lived and functionally active.
Figure 4
Figure 4
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 CD28null cells with respect to CD28+ CD4+ T-cells. IL-15 increases the cytolytic properties of CD4 + CD28null T-cells and enhances their antigen-specific responses.

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