Comparative kinetic analyses of gene profiles of naïve CD4⁺ and CD8⁺ T cells from young and old animals reveal novel age‐related alterations

Abstract

Summary It is well established that immune responses are diminished in the old. However, we still do not have a clear understanding of what dictates the dysfunction of old T cells at the molecular level. Although microarray analysis has been used to compare young and old T cells, identifying hundreds of genes that are differentially expressed among these populations, it has been difficult to utilize this information to pinpoint which biological pathways truly affect the function of aged T cells. To better define differences between young and old naïve CD4+ and CD8+ T cells, microarray analysis was performed pre- and post-TCR stimulation for 4, 12, 24 and 72 h. Our data indicate that many genes are differentially expressed in the old compared to the young at all five time points. These genes encode proteins involved in multiple cellular functions such as cell growth, cell cycle, cell death, inflammatory response, cell trafficking, etc. Additionally, the information from this microarray analysis allowed us to underline both intrinsic deficiencies and defects in signaling only seen after activation, such as pathways involving T-cell signaling, cytokine production, and Th2 differentiation in old T cells. With the knowledge gained, we can proceed to design strategies to restore the function of old T cells. Therefore, this microarray analysis approach is a powerful and sensitive tool that reveals the extensive changes seen between young and old CD4+ and CD8+ naïve T cells. Evaluation of these differences provides in-depth insight into potential functional and phenotypical differences among these populations.

Age-associated inflammation connects RAS-induced senescence to stem cell dysfunction and epidermal malignancy

“…62 Following TCR activation in aged mice, naive CD4 + T cells differentiate toward a Th2 fate. 63 Chronic Th2 inflammation is pernicious, as it recruits mast cells and eosinophils, both ECM modulators that can mediate tissue destruction and support tumor growth, 64,65 although in c-Kit − / − mice mast cells can actually confer tumor protection. 66 In addition to mast cells and eosinophils, M2-polarized macrophages commonly found in the tumor microenvironment are well documented for their ability to support tumor growth.…”

Reduced naïve CD 8 + T ‐cell priming efficacy in elderly adults

“…Indeed, contraction of the murine naïve T‐cell repertoire can impair T‐cell responses to immunodominant epitopes (Yager et al ., 2008; Valkenburg et al ., 2012). Intrinsic age‐related defects in naïve T‐cell responsiveness linked to gene expression profiles and cytokine secretion have also been documented in old mice (Mirza et al ., 2011; Decman et al ., 2012; Jiang et al ., 2013). In contrast, experimental evidence for compromised naïve T‐cell responsiveness in old humans is scarce (Goronzy & Weyand, 2013; Appay & Sauce, 2014).…”

T Cell Aging: A Review of the Transcriptional Changes Determined from Genome-Wide Analysis

“…The cumulative evidence shows that age-related alterations of transcription in T cells can be found in thymocytes (Lustig et al, 2007, 2009; Griffith et al, 2012), in peripheral mature T cells (Remondini et al, 2010), and T cell subsets (Fann et al, 2005; Mirza et al, 2011). Although neither the causes nor the consequences of all the transcriptional changes in T cells with age are currently known, the identification and validation of these age-associated changes pave a new avenue for a better understanding of cellular and functional alterations associated with aging.…”