Erythroid cell modulation of T cell function

描述(由申请人提供)：迫切需要加强对发育中的免疫系统的了解，以增进儿童和他们成年后的健康。传染病对新生儿、早产儿和五岁以下儿童的影响更为严重。幼儿可能会受到对环境抗原的不适当炎症或适应性免疫反应的影响，这可能使他们容易患上过敏性或自身免疫性疾病。最后，早期免疫系统的发育变化在儿童癌症中发挥了作用。最近的观点认为，新生儿免疫系统是“胎儿”和“成人”之间相互作用的总和，然而，人们对这些“系统”如何相互作用、过渡或影响新生儿的整体免疫知之甚少。我们研究了出生1-3周的小鼠免疫系统，因为许多方面都对妊娠中后期和新生儿的免疫系统进行了建模。在这段时间内，我们观察到了惊人的变化。例如，在T细胞完全填满脾之前，一种独特的红细胞谱系(EL)细胞在出生6天时膨胀到顶峰，在几天内成为脾中的主导群体，然后在出生21天时收缩到接近成人的水平。EL的下降伴随着脾T细胞的上升。新生儿EL与成人CD4T细胞共培养导致EL产生IL-6增加，进而导致γ干扰素减少，CD4T细胞产生IL-4增加。这些观察结果和现有证据表明，EL和T细胞都对生长因子IL-7做出反应，这使我们产生了一个新的总体假设，即在体内EL的扩张和收缩以及新生儿脾中T细胞的扩张是由对IL-7的竞争调节的，在这种情况下，EL的激活增加了EL产生的IL-6，而IL-6反过来又直接支持在新生儿生命的这一时期体内的Th-2分化。在这项R21应用中提出的工作利用了独特的基因操纵小鼠、IL-6在免疫反应调节中的作用专家的经验以及在T细胞稳态以及母体和新生儿免疫研究方面的实验室经验。这一结果有望为诊断早产儿和足月儿免疫功能障碍的方法的发展提供参考，并指导研究在新生儿期加强保护和调节不适当免疫的方法。

DESCRIPTION (provided by applicant): There is critical need for enhanced understanding of the developing immune system in order to increase the health of children and the adults they become. Infectious diseases more harshly affect the newly born, the prematurely born, and the young under the age of five. Young children can be affected by inappropriate inflammatory or adaptive immune responses to environmental antigens and this may predispose them to allergic or autoimmune disease. Finally, the altered development of the early immune system plays a role in childhood cancer. Recent thinking is that the neonatal immune system is a sum of interactions between `fetal' and `adult' components, however, little is known about how these `systems' interact, transition, or affect overall immunity in neonates. We have studied the mouse immune system between 1-3 weeks of life, as many aspects model the immune system of mid-late gestational and newborn humans. We have observed striking changes during this time frame. For example, before T cells fully populate the spleen, a unique erythrocyte lineage (EL) cell expands to a peak on days 6 of life, is the dominant population in the spleen for several days and then contracts to near adult levels by day 21 of life. The fall in EL is concomitant with rise in spleen T cells. Co-culture between neonatal EL and adult CD4 T cells led to increased EL production of IL-6 and in turn was associated with decreased γIFN and increased IL-4 production by CD4 T cells. These observations and existing evidence suggesting that both EL and T cells respond to the growth factor IL-7 lead us to the novel overall hypothesis that in vivo expansion and contraction of EL as well as expansion of T cells in the neonatal spleen is regulated by competition for IL-7 and that activation of EL in this context increases EL-produced IL-6 which in turn directly supports "Th-2" differentiation in vivo during this period of neonatal life. The work proposed in this R21 application takes advantage of unique genetically manipulated mice, the experience of an expert in the role of IL-6 in the regulation of immune responses and a laboratory experienced in both the study of T cell homeostasis and maternal and neonatal immunity. The results are expected to inform development of methods to diagnose immune dysfunction in preterm and term human infants, and guide investigation of methods to enhance protective and modulate inappropriate immunity in the neonatal period.