Aging Is Associated with Increased Human T Cell CC Chemokine Receptor Gene Expression

Leukocyte chemokine receptors (CR) are central to the pathogenesis of many human diseases, including human immunodeficiency virus-1 (HIV-1) infection. Elderly individuals infected with the HIV-1 virus have a shorter disease-free interval and worse clinic outcome. However, the reasons for this are unclear. We recently reported increased CC chemokine receptor (CCR) expression in CD4+ T cells in aged mice, but it is not known if similar changes occur in humans. In addition, it is unclear if the observed differences are related to aged-related expansion in the memory T cell compartment. In this report, we examined the effects of aging on CCR gene expression in human peripheral blood mononuclear cells (PBMCs), CD4+ T cells, and naive/memory T cells. Aging is found to be associated with increased CCR1-5 expression in PBMCs and CD4+ T cells. In addition, although the age-related increases in CCR expression occurred in both naive and memory T cells, the greatest changes were seen in the memory T cell subset. We propose that the observed aging-associated increase in T cell chemokine receptor expression may contribute to the worse clinical outcome of T cell chemokine receptor-dependent disease, such as HIV-1 infection, in the elderly.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63139/1/107999003322485071.pd

核因子-1(NF1)類似因子の補体C4遺伝子の転写活性における役割

取得学位 : 博士（医学）, 学位授与番号 : 医博甲第1202号, 学位授与年月日：平成8年3月25日,学位授与年：199

The effect of aging and caloric restriction on murine CD8+ T cell chemokine receptor gene expression

Abstract Background The mechanism explaining the increased disease susceptibility in aging is not well understood. CD8+ T cells are crucial in anti-viral and anti-tumor responses. Although the chemokine system plays a critical role in CD8+ T cell function, very little is known about the relationship between aging and the T cell chemokine system. Results In this study we have examined the effect of aging on murine CD8+ T cell chemokine receptor gene expression. Freshly isolated splenic CD8+ T cells from old C57BL/6 mice were found to have higher CCR1, CCR2, CCR4, CCR5 and CXCR5, and lower CCR7 gene expression compared to their younger cohort. Anti-CD3/anti-CD28 stimulation elicited a similar robust chemokine receptor response from young and old CD8+ T cells. Western blot analyses confirmed elevated protein level of CCR4 and CCR5 in aged CD8+ T cells. Increases in T cell CCR1 and CCR5 expression also correlate to increased in vitro chemotaxis response to macrophage-inflammatory protein-1 α(MIP-1α). Finally, caloric restriction selectively prevents the loss of CD8+ T cell CCR7 gene expression in aging to the level that is seen in young CD8+ T cells. Conclusion These findings are consistent with the notion that aging exists in a state of low grade pro-inflammatory environment. In addition, our results provide a potential mechanism for the reported aging-associated impaired T cell lymphoid homing and allograft response, and reduced survival in sepsis.http://deepblue.lib.umich.edu/bitstream/2027.42/112328/1/12979_2007_Article_43.pd

Western blot analyses of CCR4 and CCR5 protein level in aged CD8+ T cells

<p><b>Copyright information:</b></p><p>Taken from "The effect of aging and caloric restriction on murine CD8+ T cell chemokine receptor gene expression"</p><p>http://www.immunityageing.com/content/4/1/8</p><p>Immunity & ageing : I & A 2007;4():8-8.</p><p>Published online 14 Nov 2007</p><p>PMCID:PMC2200663.</p><p></p> Intracellular proteins were isolated from groups of 4–6 young and old C57Bl/6 mice. (A) Western blot analysis of CCR4 using proteins from 4 groups of young (Y1–Y4) and old (O1–O4) CD8+ T cells (total 20 young and 20 old mice). (B) Western blot analysis of CCR5 on CR8+ T cells isolated from 5 groups of young (Y1–Y5) and Old (O1–O5) mice (total 25 young and 25 old mice). (C) Histogram showing the composite results of the relative CCR4 and CCR5 protein level of old CD8+ T cells compared to young CD8+ T cells. Pairwise comparison was done for each individual sample preparation (Y1 versus O1, Y2 versus O2 etc., with the young group arbitrarily assigned the value of 1). The results are corrected for gel loading using β-actin as controls. The results are presented as mean ± SD

The effect of caloric restriction on CD8+ T cell chemokine receptor expression in aging

<p><b>Copyright information:</b></p><p>Taken from "The effect of aging and caloric restriction on murine CD8+ T cell chemokine receptor gene expression"</p><p>http://www.immunityageing.com/content/4/1/8</p><p>Immunity & ageing : I & A 2007;4():8-8.</p><p>Published online 14 Nov 2007</p><p>PMCID:PMC2200663.</p><p></p> Ribonuclease protection assays (RPAs) were done using RNA from freshly isolated splenic CD8+ T cells from young (3–4 months), old (18–20 months), and caloric restricted old (18–20 months) mice in groups of 5 animals. Density of the bands was quantified using a phosphoimager. (A) Histogram showing the composite data of 4 experiments (total 20 animals in each condition). The results represent the mean ± SEM of the relative CD8+ T cell chemokine receptor gene expression level of old and old caloric restricted mice compared to those from the young cohort (arbitrarily defined as equal to 1). (B) CCR7 expression was also determined using a custom CCR7 RPA probe. The left panel is a representative autoradiograph (lane 1 = young CD8+ T cells; lane 2 = old CD8+ T cells; lane 3 = caloric restricted old CD8+ T cells). The right panel represents the composite data of 3 RPAs with a total of 15 animals in each group. Results are presented as mean ± SEM. CR = caloric restricted. Gel loading is corrected with L32 expression

Murine CD8+ T cell chemokine receptor gene expression following T cell receptor/CD28 stimulation

<p><b>Copyright information:</b></p><p>Taken from "The effect of aging and caloric restriction on murine CD8+ T cell chemokine receptor gene expression"</p><p>http://www.immunityageing.com/content/4/1/8</p><p>Immunity & ageing : I & A 2007;4():8-8.</p><p>Published online 14 Nov 2007</p><p>PMCID:PMC2200663.</p><p></p> Autoradiographs of representative ribonuclease protection assay (RPA) showing the effect of aging and anti-CD3/anti-CD28 monoclonal antibody (mAb) stimulation on murine CD8+ T cell CCR1–5 (A) and CXCR2, 4 and 5 (B) gene expression. Lane 1 in Figure 2A and Lane 2 in Figure 2B = Young (3–4 months) unstimulated cells; Lane 2 in Figure 2A and Lane 3 in Figure 2B = Old (18–20 months) unstimulated cells; Lane 3 in Figure 2A and Lane 4 in Figure 2B = Young cells after 72 hours of anti-CD3/anti-CD28 mAb stimulation; Lane 4 in Figure 2A and Lane 5 in Figure 2B = Old cells after 72 hours of anti-CD3/anti-CD28 mAb stimulation; Lane 5 in Figure 2A and Lane 1 in Figure 2B = unprotected probe set. Composite histogram (C) of 3 RPAs using pooled RNA from a total of 15 animals in each age group is shown. Gel loading is corrected with L32 expression