The influence of age on CD4 helper activity

描述(申请人提供)：年龄对辅助者活动的影响。在老年人中，疫苗对高传染性感染(如流感)的效力大大降低。这一点极其重要，因为与年轻人相比，老年人住院和死于流感的风险要高得多。许多研究试图通过检测衰老T细胞的功能来解决这个问题。这些先前研究的缺点是，他们使用了来自老年小鼠的不同的T细胞群体，这与在年轻小鼠中发现的T细胞群体非常不同。这使得对这些实验的解释变得困难，因为年龄可能会影响T细胞总数的许多方面。事实上，在年轻人和老年人中，很可能存在着截然不同的抗原特异性CD4细胞数量。这也可能解释了已经观察到的青年和老年助手功能的差异。老龄小鼠在免疫后表现出GC形成减少和抗体亲和力成熟降低。 这项应用的目标是使用TCRTG模型来确定衰老的CD4功能的哪些方面导致B细胞辅助活性降低。这将使我们能够直接比较来自幼年和老年小鼠的同种TGCD4细胞群体的同源辅助活性。在这个模型中，与年轻细胞相比，来自老年小鼠的幼稚的TGCD4细胞在TCR刺激下产生的IL-2较少。IL-2的产生减少会导致扩张和后续效应器生成的减少，以及CD4OL表达的减少。如果我们能够确定老年人GC形成减少和随后抗体滴度下降的机制，我们就可以开始研究改进方法，最终提高老年人接种疫苗的效果。

DESCRIPTION (provided by the applicant): The influence of age on CD4 helper activity. The efficacy of vaccines for highly contagious infections, such as influenza, are greatly decreased in the elderly. This is extremely important since elderly persons exhibit a much increased risk of hospitalization and death from influenza compared to younger persons. Numerous studies have attempted to address this issue by examining the function of aged T cells. The drawback of these previous studies is that they employed heterogeneous populations of T cells from aged mice which are quite different from T cell populations found in young mice. This makes interpretation of these experiments difficult, since age may affect many aspects of the total T cell population. In fact, it is highly likely that there are dramatically different numbers of antigen-specific CD4 cells in young and aged populations. This may also account for the differences that have been observed in young and aged helper function. Aged mice have been shown to exhibit decreased GC formation and reduced antibody affinity maturation upon immunization. The goal of this application is to use a TCR Tg model to determine what aspects of aged CD4 function contribute to decreased B cell helper activity. This will allow us to directly compare the cognate helper activity of homogeneous populations of Tg CD4 cells from young and aged mice. In this model, naive Tg CD4 cells from aged mice produce less IL-2 upon TCR stimulation compared to young cells. Decreased IL-2 production leads to reduced expansion and subsequent effector generation, as well as reduced CD4OL expression. If we can determine the mechanism of decreased GC formation and subsequent reduction in antibody titers in the aged, we can then begin to examine methods for improvement and, ultimately, increase the efficacy of vaccination in the aged.