Memory T lymphocytes are characterized by their ability to mount a rapid and robust response to the recall antigen. Our previous study show that histone methylation associated chromatin state regulates the speed of transcriptional response of memory CD8 T cells. To determine what changes of the histone methylation are during CD8 T cell activation, whether histone methylation changes require cell division, and whether patterns of memory T cells are established in activated naive T cells, we conducted a parallel analysis of gene expression and histone modification in nave (TN) and memory (central, TCM, and effector, TEM) CD8 T cells after in vitro stimulation. The dramatic transcriptional changes after activation were observed in TN, TCM, and TEM CD8 T cells (20% increase and 15% decrease of total expressed genes). In parallel, we observed similar trend of histone modification of H3K4me3 and H3K9ac (but not of H3K27me3) changes in corresponding genes in CD8 T cells. Alteration of the amount of H3K4me3 after activation did not require cell division. The accessible chromatin state of the poised genes in TCM CD8 T cells were established in activated TN CD8 T cells, suggesting that activation is a necessary step of converting the chromatin from the nave closed state to the memory accessible state. Strikingly, genes with the bivalent state (high amount of both H3K4me3 and H3K27me3) were stable during activation and their expression states correlated well with histone acetylation (H3K9ac). Together, these results demonstrate that change of histone methylation (H3K4me3) is dynamic after activation without requirement of cell division in CD8 T cells and suggest that activation-induced change of chromatin in TN is part of differentiation process to establish memory T cells. MicroRNA is a key regulator of gene expression. Elevated level of chemokine expression, especially inflammatory chemokines, commonly occurs with aging, yet the mechanism underlying this age-associated change is not fully understood. Our study of the role of microRNA 125b (miR-125b) in regulating inflammatory CC chemokine 4 (CCL4) expression in human immune cells and its altered expression with aging. Resting nave CD8 T cells expressed high level of miRNA125b and low level of CCL4 whereas activated nave CD8 T cells expressed high level of CCL4 and low level of miRNA125b. Enhanced miRNA125b expression in nave CD8 T cells led to the reduction of CCL4 in response to stimulation and such action required the miRNA125b seed sequence in 3 UTR of CCL4. Extending the analysis found an inverse correlation between CCL4 mRNA and miRNA125b in all eight types of immune cells (CD4 and CD8 subsets, B cells and monocytes). Monocytes expressed the highest amount of CCL4 among tested immune cells and had a significant increase of CCL4 mRNA and decrease of miR-125b in old (≥70 yrs.) compared to the young (≤42 yrs.) adults. Finally, the reduction of miR-125b in monocytes in older adults was not due to decreased primary miR-125b transcription but may be related to the reduced maturation processing of miR-125b. Together these findings demonstrate that miRNA125b is a negative regulator of CCL4 expression and that its reduction is partially responsible for the age-related increase of the inflammatory chemokine CCL4. TCR repertoire is a vital parameter of immune competency, and its reduction believes to contribute to the age-associated decline of immune function. However, available information regarding human TCR repertoire and its age-associated changes is limited. Here, we assessed the TCRβrepertoire of CD4+ and CD8+ T cells of 8 adults (aged from 24-78), and found that TCRβdiversity of CD4+ T cells ranges from 1.8-8.2 x105 and is 3-4 times greater than that of CD8+ T cells. TCRβCDR3 sequences were distinct between CD4+ and CD8+ T cells, with distinct patterns of preferential amino acid usage observerd in CD4+ and CD8+ T cell. Longitudinal study of 5 adults (aged from 45-94 and 2 time points separated by an average of 8.4 years) showed that reduction of TCRβdiversity and expansion of abundant TCRβclones occurred from middle to old age (45-75 years old) but not in very old age (80-94 years old). Together, these findings reveal the distinct features and the precise changes of TCRβrepertoire with age, and could potentially serve as an evaluation of the competency of the adaptive immune system and a guide of clinical applications.
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