Age-Related Gene Alteration in Naïve and Memory T cells Using Precise Age-Tracking Model

Abstract

In aged individuals, age-related changes in immune cells, especially T cell deficiency, are associated with an increased incidence of infection, tumor, and autoimmune disease, as well as an impaired response to vaccination. However, the features of gene expression levels in aged T cells are still unknown. Our previous study successfully tracked aged T cells generated from one wave of developing thymocytes of young age by a lineage-specific and inducible Cre-controlled reporter (TCRδCreERR26ZsGreen mouse strain). In this study, we utilized this model and genome-wide transcriptomic analysis to examine changes in gene expression in aged naïve and memory T cell populations during the aging process. We identified profound gene alterations in aged CD4 and CD8 T cells. Both aged CD4+ and CD8+ naïve T cells showed significantly decreased organelle function. Importantly, genes associated with lymphocyte activation and function demonstrated a significant increase in aged memory T cells, accompanied by upregulation of immunosuppressive markers and immune checkpoints, revealing an abnormal T cell function in aged cells. Furthermore, aging significantly affects T cell survival and death signaling. While aged CD4 memory T cells exhibited pro-apoptotic gene signatures, aged CD8 memory T cells expressed anti-apoptotic genes. Thus, the transcriptional analysis of gene expression and signaling pathways in aged T cell subsets shed light on our understanding of altered immune function with aging, which will have great potential for clinical interventions for older adults.

The Role of Cysteine Peptidases in Hematopoietic Stem Cell Differentiation and Modulation of Immune System Function

“…The accumulation of senescent CD8+ T cells influences the quality of the memory T-cell pool, impairs the capacity to respond to vaccination, and is highly associated with age-related diseases (231). A recent study showed that Serpina3g (that encodes Spi2A and is necessary for counteracting the pro-apoptotic effects of CatB and the maintenance of long-term memory CD8+ T cells) expression was increased in both old CD8+ central memory (TCM) and effector memory (TEM) cells, supporting the long-term survival of CD8 T memory cells (232). Furthermore, a cohort of healthy elderly volunteers exhibited no differences in CatB activity in their granulocytes, monocytes, or lymphocytes but exhibited increased CatC (DPP I) activity in their lymphocytes, compared with young controls (233).…”

“…Treatment of Leishmania major -infected BALB/c mice with a specific inhibitor of Cathepsin B (CA074) augmented the Th1 response (232). Th2…”

Immunosenescence and Autoimmunity: Exploiting the T-Cell Receptor Repertoire to Investigate the Impact of Aging on Multiple Sclerosis

“…To date, the majority of HTS studies on TCR repertoire in immunosenescence has been performed in healthy individuals. Recent findings highlighted that the healthy TCR repertoire is strongly impacted by antigens encountered over lifetime and consequently dwindles (3,4,10,12), and such variations can be better appreciated in memory T cells after the age of 40 (4); furthermore, the shrinkage of TCR repertoire diversity correlates with the natural involution of the naïve T-cell compartment (4,7,13). TCR repertoire analysis in elderly also showed great potential unrevealing molecular markers of longevity, as Britanova et al (4) found that healthy people older than 80 years are characterized by a broader TCR repertoire diversity compared to individuals of 65 y.o.…”

“…Over time, the T-cell compartment gradually switches towards a homeostatic maintenance of the existing cells rather than generating new ones, as reflected by the reduction of naïve cells ( 3 , 4 ). In these circumstances memory T cells become prevalent, showing changes in either immunophenotype ( 5 , 6 ) and gene expression ( 7 , 8 ). The composition of the memory T-cell compartment in advanced age is closely linked to the individual immunological history, e.g.…”

Skin Aging, Cellular Senescence and Natural Polyphenols

“…It has been suggested that age-related immune dysfunction may correlate with defects (either increases or decreases) in apoptosis among different T cell subpopulations [ 151 ]. A recent study using TCRδ CreER R26 ZsGreen double transgenic mice showed that, whereas aged CD4+ memory T cells were shown to exhibit pro-apoptotic gene signatures, aged CD8+ memory T cells expressed anti-apoptotic genes [ 169 ]. Consistently, an increased expression of programmed death protein 1 (PD-1) on CD4+ T cells has been shown in the skin and peripheral blood populations of these cells in older adults, which renders them more susceptible to inhibition [ 170 ].…”