BackgroundAlterations in the number and composition of lymphocytes and their subsets in blood are considered a hallmark of immune system aging. However, it is unknown whether the rates of change of lymphocytes are stable or change with age, or whether the inter-individual variations of lymphocyte composition are stable over time or undergo different rates of change at different ages. Here, we report a longitudinal analysis of T- and B-cells and their subsets, and NK cells in the blood of 165 subjects aged from 24 to 90 years, with each subject assessed at baseline and an average of 5.6 years follow-up.ResultsThe rates of change of T-(CD4+ and CD8+) and B-cells, and NK cells were relative stable throughout the adult life. A great degree of individual variations in numbers of lymphocytes and their subsets and in the rates of their changes with age was observed. Among them, CD4+ T cells exhibited the highest degree of individual variation followed by NK cells, CD8+ T cells, and B cells. Different types of lymphocytes had distinct trends in their rates of change which did not appear to be influenced by CMV infection. Finally, the rates of CD4+, CD8+ T cells, naive CD4+ and naïve CD8+ T cells were closely positively correlated.ConclusionOur findings provide evidence that the age-associated changes in circulating lymphocytes were at relative stable rates in vivo in a highly individualized manner and the levels of selected cytokines/cytokine receptors in serum might influence these age-associated changes of lymphocytes in circulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12979-016-0079-7) contains supplementary material, which is available to authorized users.

Chemokines play a pivotal role in regulating the immune response through a tightly controlled expression. Elevated levels of inflammatory chemokines commonly occur with aging but the mechanism underlying this age-associated change is not fully understood. Here, we report 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. We first analyzed the mRNA level of CCL4 in eight different types of immune cells including CD4 and CD8 T-cell subsets (naïve, central and effector memory), B cells and monocytes in blood from both young (≤42 years) and old (≥70 years) adults. We observed that monocytes and naïve CD8 T cells expressed higher levels of CCL4 and exhibited an age-related increase in CCL4. We then found the level of miR-125b was inversely correlated with the level of CCL4 in these cells, and the level of miR-125b was reduced in monocytes and naïve CD8 T cells of the old compared to the young adults. Knock-down of miR-125b by shRNA in monocytes and naïve CD8 T cells led to an increase of CCL4 protein, whereas enhanced miR-125b expression by transfection in naïve CD8 T cells resulted in a reduction of the CCL4 mRNA and protein in response to stimulation. Finally, we demonstrated that miR-125b action requires the ‘seed’ sequence in 3′UTR of CCL4. Together these findings demonstrated that miR-125b is a negative regulator of CCL4 and its reduction is partially responsible for the age-related increase of CCL4.

The tumor suppressor protein p53 is unstable in quiescent cells and undergoes proteosomal degradation. Under conditions of cellular stress, p53 is rapidly stabilized by post-translational modification, thereby escaping degradation and translocating to the nucleus where it activates genes related to cell cycle arrest or apoptosis. Here, we report that the transcription elongation factor Ell3 sensitizes luminal type-cancer cell line, MCF7, which have wild-type p53, to the chemotherapeutic agent cis-diamminedichloroplatinum(II) (CDDP) by stabilizing p53. Overexpression of Ell3 in MCF7 cells suppressed the MDM2-mediated ubiquitin-dependent degradation pathway. In addition, Ell3 promoted binding of p53 to NADH quinone oxidoreductase 1, which is linked to the ubiquitin-independent degradation of p53. We found that Ell3 activates interleukin-20 (IL20) expression, which is linked to the ERK1/2 signaling pathway. Chemical inhibition of ERK1/2 signaling or molecular suppression of IL20 revealed that the ERK1/2 signaling pathway and IL20 are the main causes of p53 stabilization in Ell3-overexpressing MCF7 cells. These findings suggest that the ERK1/2 pathway can be targeted in the rational development of therapies to induce chemosensitization of breast cancer cells.

Genes containing both histone methylation H3K4me3 and H3K27me3 markers at the promoter are so called bivalent genes that have been implicated in stem cell differentiation and function. Our previous study identified several dozen bivalent genes in memory CD8 T cells (central memory, TCM and effector memory, TEM). But the role of bivalent genes in CD8 T cells is not understood. Our current focus is to determine the characteristics and functions of these bivalent genes during CD8 memory T cell activation. We used freshly isolated TCM and TEM from human blood that were stimulated by anti-CD3 plus anti-CD28 in vitro, and analyzed histone methylation and mRNA levels of these bivalent genes in resting and activated CD8 memory T cells. Our preliminary results showed that the bivalent status of most genes was stable but corresponding mRNA change was more detectable. We also identified a few bivalent genes whose status changed to become “monovalent”; either H3K4me3 or H3K27me3 after activation. We plan to determine the functional role of these bivalent genes that are altered after activation, and whether the bivalent histone methylation is present on a single gene allele or on two different alleles by sequential ChIP. Our study will shed new insight into the details of histone methylation on gene loci and the function of these bivalent genes in memory CD8 T cells. “This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging “