Role of Telomere In Human Lymphocyte Function and Aging

端粒在人类淋巴细胞功能和衰老中的作用

• 批准号: 8736615
• 负责人: Nan ping Peter Weng
• 金额: $ 30.45万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8736615
• 关键词: Address; Affect; Age; Aging; Antibody Formation; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Blood Cells; CD28 gene; CD8B1 gene; Cells; Chromosomes; Cross-Sectional Studies; Elderly; Exhibits; Factor Analysis; Goals; Health; Human; Immune response; In Vitro; Individual; Influenza; Length; Leukocytes; Longevity; Lymphocyte; Lymphocyte Function; Measurement; Measures; Molecular; Obesity; Peripheral Blood Mononuclear Cell; Rest; Role; T-Lymphocyte; Telomerase; Vaccines; adaptive immunity; age related; follow-up; human subject; immune function; in vivo; influenza virus vaccine; longitudinal analysis; monocyte; response; seasonal influenza; telomere

Telomeres are the tip of chromosome and serve essential function in chromosome integrity and in regulating cell replicative lifespan. Previous cross-sectional analyses of telomere length in blood leukocytes show an age-related shortening, but the actual in vivo change of telomere length and its relationship with telomerase, cell composition of leukocytes, and health conditions is not fully addressed. We have conducted a longitudinal analysis of telomere length in peripheral blood mononuclear cells (PBMCs), lymphocytes, and monocytes at zero (n=220) and at five- (n=216) and twelve- year (n=158) follow-up of the human subjects. In PBMCs, we observed telomere length of decrease in 34% and 46%, no detectable changes in 56% and 47%, and increase in 10% and 7% of all subjects for 5- and 12-year follow-up, respectively. The rate of telomere change was distinct for T- and B-cell and monocytes for an individual. Furthermore, telomerase activity declined with age in resting and activated T cells, and resting but not activated B cells. Age-related changes in percentages of naive (decrease) and CD28- (increase) T cells were positively and negatively correlated to telomere length in T cells, respectively. Finally, a significant portion of the observed telomere attrition in T cells with age was explained by declined telomerase activity, decreased naive cells, and the presence of specific health conditions such as adiposity. These findings show that reduction of telomere length of PBMC with age in vivo occurs at different rates in different subjects and that telomere length of T cells is affected by telomerase activity, nave T cell percentage, and changes in health conditions. To understand the role of telomere length in the age-associated decline of immune function in vivo. We compared immune responses against influenza in healthy older adults who had relatively short or long telomere lengths in peripheral blood mononuclear cells (PBMCs). Our findings showed that: 1) B cells from individuals with a robust antibody response to the seasonal influenza vaccine had significantly longer telomeres than those from individuals with a poor antibody response; 2) monocyte derived antigen presenting cells (APC) from both short and long telomere groups were able to induce similar expansions of influenza reactive CD8+ T cells; 3) influenza reactive CD8+ T cells from the long telomere group exhibited significantly better expansion in response to the influenza antigen (M1) in vitro compared to those from the short telomere group; and 4) direct measurement of telomere length of M1 reactive CD8+ T cells demonstrated that cells with significantly more divisions had significantly longer telomeres compared to cells with few divisions. Together, these findings show that telomere length is positively associated with a robust adaptive immune response and suggest that telomeres may have an important role in the age-associated decline of adaptive immunity against influenza infection.

端粒是染色体的尖端，在染色体完整性和调节细胞复制寿命方面起着重要功能。 先前对血清细胞端粒长度的横截面分析表明，端粒长度的实际体内变化及其与端粒酶的关系，白细胞的细胞组成和健康状况的实际变化尚未完全解决。我们已经对外周血单核细胞（PBMC），淋巴细胞和单核细胞的端粒长度进行了纵向分析（零= 220），五（n = 216）和十二年（n = 158）（n = 158）。在PBMC中，我们观察到34％和46％的端粒减小长度，分别为56％和47％的可检测变化，分别为5年和12年随访的所有受试者的10％和7％增加。对于个体的T和B细胞和单核细胞的端粒变化速率是不同的。此外，端粒酶活性随着静息和激活的T细胞的年龄而下降，静止而不是激活的B细胞。与年龄相关的幼稚（降低）和CD28-（增加）T细胞的变化分别与T细胞中T细胞的端粒长度呈正相关。最后，通过年龄的T细胞中观察到的端粒损耗的很大一部分是通过端粒酶活性下降，幼稚细胞降低以及特定健康状况（如肥胖性）的存在来解释的。这些发现表明，随着年龄的体内，PBMC的端粒长度的减小在不同受试者中以不同的速率发生，并且T细胞的端粒长度受端粒酶活性，中含T细胞百分比以及健康状况的变化的影响。 了解端粒长度在体内免疫功能下降中的作用。我们比较了对外周血单核细胞（PBMC）中端粒长度相对较短或长的健康老年人中对流感的免疫反应。 我们的发现表明：1）来自对季节性流感疫苗的稳健抗体反应的个体的B细胞的端粒明显更长。 2）来自短端粒和长端粒派生的单核细胞衍生的抗原呈递细胞（APC）能够诱导类似的流感反应性CD8+ T细胞的膨胀； 3）与短端粒组相比，来自长端粒组的流感反应性CD8+ T细胞在体外对流感抗原（M1）的响应表现出明显更好的膨胀。 4）直接测量M1反应性CD8+ T细胞的端粒长度表明，与几乎没有分裂的细胞相比，具有更多分裂的细胞的端粒明显更长。总之，这些发现表明，端粒长度与强大的适应性免疫反应呈正相关，并表明端粒可能在与流感感染的适应性免疫相关的下降中具有重要作用。