Novel Interactions Between the Immune and Neuroendocrine Systems

随着年龄的增长，获得性免疫、T淋巴细胞输出和T细胞受体(TCR)谱系的收缩下降在很大程度上归因于胸腺退化。随着年龄的增长，胸腺功能的丧失可能是由于胸腺前体细胞的数量减少以及胸腺微环境中关键的细胞因子和激素的丧失。我们以前已经证明，促食欲素激素Ghrelin和促厌食激素Leptin由免疫细胞表达，并调节T细胞的激活和炎症。我们目前的工作表明，随着年龄的增长，胸腺内Ghrelin和Ghrelin受体的表达都会减少。老年小鼠注射Ghrelin可显著改善胸腺结构和胸腺细胞数量的增龄性变化，增加新近的胸腺移行者(RTES)，并改善外周血CD4和CD8T细胞的TCR多样性。Ghrelin在衰老过程中诱导的胸腺生成与早期胸腺细胞前体细胞(ETP)和骨髓来源的阴性SCA-1，c-kit High(LSK)细胞的增强有关。此外，Ghrelin和GHS-R缺乏的小鼠表现出与年龄相关的胸腺退化增强，胸腺生成减少，LSK造血干细胞室收缩。在GHS-R基因敲除小鼠中观察到的胸腺加速退化反映在外周T淋巴细胞亚群TCR谱系的主要扰动上。同样，将瘦素注射到老年小鼠体内，对胸腺前体细胞和胸腺退化的影响与Ghrelin和垂体激素生长激素(GH)相似。荷尔蒙诱导的变化似乎是通过不同的信号通路来调节的。我们的发现证明了这些激素及其受体在胸腺生物学中的新作用，并表明利用这些激素途径重建老年人和免疫低下受试者的胸腺功能可能有治疗益处。此外，我们发现这些激素调节多种白细胞功能，并支持存在一个涉及食欲和厌食激素的功能性免疫调节网络，控制免疫细胞的激活和分化、造血和细胞存活。最近的工作集中在这些激素对T细胞信号和分化的影响，以及这些激素在控制炎性细胞因子信号和激活中的作用。

The decline in adaptive immunity, T lymphocyte output and the contraction of the T cell receptor (TCR) repertoire with age is largely attributable to thymic involution. The loss of thymic function with age may be due to diminished numbers of thymic progenitors and the loss of critical cytokines and hormones from the thymic microenvironment. We have previously demonstrated that the orexigenic peptide hormone, ghrelin, and the anorexigenic hormone, leptin, are expressed by immune cells and regulate T-cell activation and inflammation. Our current work has demonstrated that both ghrelin and ghrelin receptor expression within the thymus diminishes with progressive aging. Infusion of ghrelin into old mice significantly improves the age-associated changes in thymic architecture and thymocyte counts with an increase in recent thymic emigrants (RTEs) and improvement of TCR diversity of peripheral CD4+ and CD8+ T cells. The ghrelin-induced thymopoiesis during aging was associated with enhancement of early thymocyte progenitors (ETP) and bone marrow-derived lineage negative sca-1, c-kit high (LSK) cell. Furthermore, the ghrelin and GHS-R deficient mice displayed enhanced age-associated thymic involution with reduced thymopoiesis and contraction of LSK hematopoietic stem cell compartment. The accelerated thymic involution observed in GHS-R knock out mice was reflected in major perturbations in the TCR repertoire of peripheral T lymphocyte subsets. Similarly, leptin infusion into old mice demonstrated similar effects on thymic progenitors and thymic involution as was observed with ghrelin and the pituitary hormone, growth hormone (GH). It appears that hormone-induced changes appear to be mediated via distinct signaling pathways. Our findings demonstrate a novel role for these hormones and their receptors in thymic biology and suggest a possible therapeutic benefit of harnessing these hormonal pathways in reconstitution of thymic function in elderly and in immunocompromised subjects. Moreover, we have found that these hormones modulate a variety of leukocyte functions and support the existence of a functional immunoregulatory network involving orexigenic and anorexigenic hormones in controlling immune cellular activation and differentiation, hematopoiesis and cell survival. Recent work has focused on the effects of these hormones on T-cell signaling and differentiation and the role of these hormones in the control of inflammatory cytokine signaling and activation.