Dysregulation of B cell homeostasis in aged mice

新的淋巴细胞必须不断补充长寿的成熟淋巴细胞，以最大限度地提高免疫库的多样性和反应性。随着个体年龄的增长，免疫功能普遍下降，免疫衰老，这逐渐限制了对新抗原挑战的反应;防止老年人有效接种疫苗并增加其对感染的易感性。一种提出的免疫衰老机制是衰老减少了初级淋巴器官中的淋巴细胞生成，减少了幼稚B和T细胞的产生。我们已经使用过继转移模型来确定在抗原暴露的情况下幼稚B细胞的复制潜力。我们发现幼稚B细胞的复制在B细胞缺陷的受者中是最大的，但在老年受者中复制显著降低，尽管他们是B细胞缺陷的。这些初步的结果被用来制定一个更具竞争力的观点免疫衰老：我们假设，新产生的幼稚B细胞进入池的长寿B细胞的老年微环境的变化受到限制。因为幼稚B细胞是对新抗原的主要应答者，所以抑制它们的进入降低了免疫库和免疫应答的多样性。本试验项目的目的是初步评估年龄依赖性稳态失调的机制基础。我们将：（1）确定B细胞归巢或定位于脾内是否受老化影响或由于老化微环境的其它变化，（2）老化B细胞的定量或定性变化是否是抑制性的，和（3）确定老化T细胞是否抑制幼稚B细胞进入和/或扩增。

New lymphocytes must constantly replenish the long-lived mature lymphocyte to maximize immune repertoire diversity and responsiveness. As individuals age there is a generalized diminution of immune function, immunosenescence, which progressively restricts responses to new antigenic challenges; preventing efficient vaccination of the elderly and increasing their susceptibility to infection. One proposed mechanism of immunosenescence is that aging diminishes lymphopoiesis in the primary lymphoid organs reducing the production of naive B and T cells. We have used an adoptive transfer model to determine the replicative potential of naive B cells in the absence of antigen exposure. We find replication of naive B cells is greatest in B ell deficient recipients but 6that replication was significantly reduced in aged recipients despite their being B cell deficient. These preliminary results were used to formulate a more competitive view of immunosenescence: we hypothesize that newly produced naive B cells are restricted from entering the pool of long-lived B cells by changes in the aged microenvironment. Because naive B cells are the major responders to new antigens, the inhibition of their entry reduces the diversity of the immune repertoire and immune responsiveness. The goals of this pilot project are to assess preliminary the mechanistic basis for age dependent homeostatic dysregulation. We will: (1) determine if B cell homing to or localization within the spleen is affected by aging or is due to other changes in the aged microenvironment, (2) if quantitative or qualitative changes in aged B cells are inhibitory, and (3) establish if aged T cells inhibit naive B cell entry and/or expansion.