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  • CD is a key co stimulation


    CD28 is a key co-stimulation surface marker that can be detected in all peripheral T PRT062070 in newborns, and the proportion of CD28bearing T cells reduces progressively with age [reviewed by (Fagnoni et al., 1996; Weng et al., 2009)]. Therefore, CD28nullCD8+ T cells are one of the most acknowledged cellular hallmarks during T cell aging. Until now, the molecular regulation associated with the origins of CD28nullCD8+ T cells and their age-related expansion have been far from clear. Moreover, a unique subset of CD28nullCD8+ T cells are characterized as oligo-clonally expanded and terminally differentiated in the peripheral blood in the elderly population [Reviewed by (Mou et al., 2014; Strioga et al., 2011)]. Of note, the subset population that forms the predominant clonal expansion of CD28nullCD8+ T cells are responsive to episodes of persistent CMV Weekes, 1999 #288 . An increased proportion of CD28nullCD8+ T cells and an accumulation of CMV-specific CD8+ T cells are two of the parameters that are included in the cluster of parameters comprising the Immune Risk Phenotypes, which weakly predict near-mortality in the elderly over 85 years of age (Weekes et al., 1999; Wikby et al., 2005). Latent CMV, with its huge DNA size and complicated protein structure, hides in the bone marrow, with episodically undetected reactivation in peripheral blood. To date, hundreds of CMV episodes, which can induce clonal expansion, have been identified to be recognized by heterogeneous HLA-restricted T-cell receptors (TCRs) in the peripheral blood. Among them, the proportion of CMVpp65-specific clonal expansion, which was found to be the top frequently recognized episode, was <30% Slezak, 2007 #397 . Moreover, the presence of >200 different T cell subsets with high combinatorial diversity identified in the peripheral blood window (Newell et al., 2012) highlight the difficulty of screening biomarkers for T cell aging. Because of this complexity, biomarkers for T cell aging can be considered a kind of “dark matter” in the study of immunity aging in the general elderly population. Researchers believe that these markers exist but do not yet have any real leads as to what they might be. In the present study, based on the phenotypic overlap between CD28nullCD8+ T cells and CMVpp65-specific CD8+ T cells, we established a strategy of stepwise screening and validation to search for subclinical hallmarks of adaptive CD8+ T cell aging. We used stepwise screening and intracellular validation to identify the hallmarks in individuals over 80 years of age who were also CMV carriers. For our hallmark candidate, we chose long noncoding RNA (lncRNA), which has been increasingly found to play a critical role in the regulation of both aging and adaptive immunity to viruses [reviewed by (Grammatikakis et al., 2014; Imam et al., 2015; Aune et al., 2016)]. Here, we screened for age-accumulated lncRNAs and their immunity-related target genes in CD28nullCD8+ T cells and CMVpp65CD8+ T cells from CMV carriers with very advanced age to identify potential biomarkers of CD8+ T cell aging.
    Discussion It is highly challenging to screen for biomarkers that address the entangled contributions of persistent virus enhancement on age-accumulated T cell aging. (Waaijer et al., 2017) (Jackson et al., 2017). As the process of T cell aging is generally subclinical and accumulative by age, the intriguingly overlapping phenotypes between CD28nullCD8+ T cells and CMVpp65CD8+ T cells (Weekes et al., 1999) have addressed an idea “window” for screening the clinical hallmarks of CD8+ T cell aging. In the present study, we initially “confined” the clinical homogeneity by selecting a representative subpopulation from an extremely heterogeneous general elderly population to ensure successful screening. Then, we intensively selected subclinical CMV carriers of very advanced age who had experienced a long period of immune aging to better reflect the accumulation of T cell aging by the episodic enhancement of CMV persistence.