Resistance to age-dependent thymic atrophy in long-lived mice that are deficient in pregnancy-associated plasma protein A
Resistance to age-dependent thymic atrophy in long-lived mice that are deficient in pregnancy-associated plasma protein A
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DOI：
10.1073/pnas.0807025106
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发表时间：
2009-07-07
影响因子：
11.1
通讯作者：
Conover, Cheryl A.
中科院分区：
文献类型：
--
作者：
Vallejo, Abbe N.;Michel, Joshua J.;Conover, Cheryl A.
妊娠相关血浆蛋白A（PAPPA）是一种金属蛋白酶，控制胰岛素样生长因子（IGF）的组织可用性。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，我们研究了PAPPA（-/-）小鼠及其野生型同窝仔在无特定病原体条件下随年龄增长而饲养的自然免疫生态学。尽管野生型小鼠表现出典型的年龄依赖性胸腺萎缩，但18月龄PAPPA（-/-）小鼠保持离散的胸腺皮质和髓质，其中CD 4（+）CD 8（+）胸腺细胞密集，能够分化为单阳性CD 4和CD 8 T细胞。老年PAPPA（-/-）小鼠具有高水平的T细胞受体切除环，并且具有富含胸腺播种祖细胞亚群的骨髓。PAPPA（-/-）小鼠具有总体上较大的初始T细胞池，并且还表现出与野生型小鼠相似的CD 44（+）CD 43（+）记忆T细胞的年龄依赖性积累。然而，老年PAPPA（-/-）小鼠的CD 43（+）T细胞亚群具有显著较低的1B 11和S7流行率，已知糖基化同种型在正常衰老时抑制T细胞活化。在细胞活化的生物测定中，老年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，并且还引起自体B细胞以与年轻野生型小鼠相当的水平产生IG。这些数据表明健康长寿的IGF免疫轴。通过靶向操纵PAPPA来控制胸腺中IGF的可用性可能是维持出生后发育和衰老期间免疫稳态的一种方法。
Pregnancy-associated plasma protein A (PAPPA) is a metalloproteinase 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 homeostasis during postnatal development and aging.