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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Resistance to age-dependent thymic atrophy in long-lived mice that are deficient in pregnancy-associated plasma protein A
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Resistance to age-dependent thymic atrophy in long-lived mice that are deficient in pregnancy-associated plasma protein A

机译：缺乏妊娠相关血浆蛋白A的长寿小鼠对年龄依赖性胸腺萎缩的抵抗力

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摘要

Pregnancy-associated plasma protein A (PAPPA) is a metal-loproteinase that controls the tissue availability of insulin-like growth factor (IGF). Homozygous deletion of PAPPA in mice leads to lifespan extension. Since immune function is an important determinant of individual fitness, we examined the natural immune ecology of PAPPA~(-/-) mice and their wild-type littermates reared under specific pathogen-free condition with aging. Whereas wild-type mice exhibit classic age-dependent thymic atrophy, 18-month-old PAPPA~(-/-) mice maintain discrete thymic cortex and medulla densely populated by CD4~+CD8~+ thymocytes that are capable of differentiating into single-positive CD4 and CD8 T cells. Old PAPPA~(-/-) mice have high levels of T cell receptor excision circles, and have bone marrows enriched for subsets of thymus-seeding progenitors. PAPPA-'- mice have an overall larger pool of naive T cells, and also exhibit an age-dependent accumulation of CD44~+CD43~+ memory T cells similar to wild-type mice. However, CD43~+ T cell subsets of old PAPPA~(-/-) mice have significantly lower prevalence of 1B11 and S7, glycosylation isoforms known to inhibit T cell activation with normal aging. In bioassays of cell activation, splenic T cells of old PAPPA~(-/-) mice have high levels of activation antigens and cytokine production, and also elicit Ig production by autologous B cells at levels equivalent to young wild-type mice. These data suggest an IGF-immune axis of healthy longevity. Controlling the availability of IGF in the thymus by targeted manipulation of PAPPA could be a way to maintain immune ho-meostasis during postnatal development and aging.
机译：妊娠相关血浆蛋白A（PAPPA）是一种金属蛋白酶，可控制胰岛素样生长因子（IGF）的组织利用率。小鼠中PAPPA的纯合缺失导致寿命延长。由于免疫功能是个体适应性的重要决定因素，因此我们研究了PAPPA〜（-/-）小鼠及其在特定无病原体条件下随衰老饲养的野生型同窝仔的自然免疫生态。野生型小鼠表现出经典的年龄依赖性胸腺萎缩，而18个月大的PAPPA〜（-/-）小鼠则保持离散的胸腺皮质和髓质，其中CD4〜+ CD8〜+胸腺细胞密集分布，能够分化为单核细胞。阳性CD4和CD8 T细胞。老的PAPPA〜（-/-）小鼠具有高水平的T细胞受体切除环，并且具有丰富的胸腺播种祖细胞亚群的骨髓。 PAPPA -'-小鼠总体上具有较大的幼稚T细胞库，并且与野生型小鼠相似，还表现出CD44〜+ CD43〜+记忆T细胞的年龄依赖性积累。然而，老PAPPA〜（-/-）小鼠的CD43〜+ T细胞亚群的1B11和S7患病率明显较低，已知糖基化同工型可抑制正常衰老的T细胞活化。在细胞活化的生物测定中，老的PAPPA-（-/-）小鼠的脾T细胞具有高水平的活化抗原和细胞因子产生，并且还通过自体B细胞以与年轻野生型小鼠相当的水平引起Ig产生。这些数据表明健康长寿的IGF免疫轴。通过有针对性的操纵PAPPA来控制胸腺中IGF的可用性可能是在出生后发育和衰老过程中维持免疫稳态的一种方法。

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  • 作者

    Abbe N. Vallejo; Joshua J. Michel; Laurie K. Bale; Bonnie H. Lemster; Lisa Borghesi; Cheryl A. Conover;

  • 作者单位

    Departments of Pediatrics, Pittsburgh, PA 15201 Departments of lmmunology, Pittsburgh, PA 15201 Departments of Children's Hospital of Pittsburgh, Pittsburgh, PA 15201 Departments of Pittsburgh Cancer Institute, Pittsburgh, PA 15201;

    Departments of Pediatrics, Pittsburgh, PA 15201 Departments of Children's Hospital of Pittsburgh, Pittsburgh, PA 15201;

    Endocrine Research, Mayo Clinic, Rochester, MN 55905;

    Departments of Pediatrics, Pittsburgh, PA 15201 Departments of Children's Hospital of Pittsburgh, Pittsburgh, PA 15201;

    Departments of lmmunology, Pittsburgh, PA 15201 Departments of Pittsburgh Cancer Institute, Pittsburgh, PA 15201;

    Endocrine Research, Mayo Clinic, Rochester, MN 55905;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    aging; insulin-like growth factor; T cells; thymus;

    机译：老化;胰岛素样生长因子;T细胞;胸腺;

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