Human immune system layering and the neonatal response to vaccines

描述(申请人提供)：哺乳动物免疫系统的发育通常被认为是以线性方式发生的，从不成熟到成熟是抗原暴露的函数。然而，之前在鸟类和老鼠身上的发现表明，这种观点过于简单化了。因此，在这些物种中，发育中的免疫系统似乎以一种独立于抗原暴露的方式“分层”，最初是一个多谱系的胎儿系统，出生后被一个在解剖学和生物学上不同的多谱系系统所取代。如果是这样，那么发育有序和独特的造血干/祖细胞(HSPC)可以在不同的发育阶段产生不同的淋巴细胞谱系。在正在进行的实验中，我们发现这种免疫系统“分层”发生在人类身上。我们的初步数据表明，人类胎儿对外源抗原的强烈免疫反应可以被抗原特异性Tregs主动抑制，这些胎儿Tregs来自胎儿特有的T细胞谱系，并且这个谱系是由不同于成人的HSPC产生的。这些数据表明，人类的免疫系统由两种不同的波组成：一种是由存在于胎儿肝脏和骨髓中的“胎儿”HSPC产生的，另一种是由后来驻留在骨髓中的取代“成人”HSPC的HSPC产生的。前者产生一种免疫系统，容易对外来抗原产生耐受性反应。后者产生的免疫系统更有可能产生免疫反应(例如，包括细胞毒性T细胞和中和抗体)。鉴于这些发现，我们假设免疫系统个体发育的生理分层导致出生时胎儿和成人型T细胞的比例处于正常范围，一些新生儿表现出比其他新生儿更高的胎儿T细胞比例；那些胎儿/成人T细胞比例高的新生儿将在常规儿童免疫中产生主要的Th2反应。这些假设将在以下特定目标的实验中得到解决：(1)确定足月新生儿脐血中胎儿至成人T细胞的正常范围；以及(2)确定那些胎儿/成人T细胞比例高的足月新生儿是否更有可能对常规儿童疫苗产生Th2极化的免疫反应。如果这项探索性研究揭示了出生时胎儿和成人T细胞比例的正常变化，如果这种变化与儿童接种疫苗后Th2扭曲直接相关，那么旨在出生时将这一比例更多地改变为成人血统的方法可能会为相当数量的新生儿提供好处。 公共卫生相关性：这些探索性研究与公共卫生相关有两个原因。首先，它们可能提供概念验证证据，证明在人类新生儿中存在一定范围的免疫系统“分层”。其次，他们可能会证明，这一范围本身与新生儿抵御感染和对疫苗的反应能力的差异有关(也可能是其原因)。

DESCRIPTION (provided by applicant): The development of the mammalian immune system is typically thought to occur in a linear fashion, from immaturity to maturity as a function of antigen exposure. Previous findings in birds and in mice, however, indicate that this view is oversimplified. Thus, in these species, the developing immune system appears to be "layered" in a manner that is independent of antigen exposure, beginning as a multilineage fetal system that is replaced by an anatomically and biologically distinct multilineage system after birth. If so, then developmentally ordered and unique hematopoietic stem/progenitor cells (HSPC) could give rise to distinct lymphocyte lineages at different stages of development. In ongoing experiments, we have found that such immune system "layering" occurs in humans. Our preliminary data show that a vigorous human fetal immune response to exogenous antigens can be actively suppressed by antigen-specific Tregs, that these fetal Tregs are derived from a fetal-specific lineage of T cells, and that this lineage is generated by an HSPC that is distinct from that found in adults. These data suggest that the human immune system is comprised of two distinct waves: one generated from a "fetal" HSPC that exists in utero in the fetal liver and bone marrow, and another generated from a superseding "adult" HSPC that resides in the bone marrow at later time points. The former gives rise to an immune system that is prone to deliver a tolerogenic response to foreign antigens. The latter gives rise to an immune system that is more likely to generate an immunoreactive response (e.g., one including cytotoxic T cells and neutralizing antibodies). Given these findings, we hypothesize that physiologic layering of immune system ontogeny leads to a normal range in the ratio of fetal- to adult-type T cells at birth, with some neonates exhibiting a higher fraction of fetal T cells than others; and that those with a high ratio of fetal/adult T cells will generate predominant Th2 responses to routine childhood immunizations. These hypotheses will be addressed in the experiments of the following Specific Aims: (1) to determine the normal range of fetal to adult T cells in the umbilical cord blood of the full term neonate; and (2) to determine whether those full term neonates with a high ratio of fetal/adult T cells are more likely to generate a Th2-polarized immune response to routine childhood vaccines. Should this exploratory study reveal normal variation in the ratio of fetal to adult T cells at birth and should such variation be directly related to a Th2 skew after childhood vaccination, modalities aimed at changing this ratio more towards the adult lineage at birth may provide benefit to a substantial number of newborns. PUBLIC HEALTH RELEVANCE: These exploratory studies are relevant to public health for two reasons. First, they may provide proof-of- concept evidence for the existence of a range in the extent of immune system "layering" in human neonates. Secondly, they may demonstrate that this range is itself related to (and possibly causal of) differences in the ability of neonates to withstand infections and to respond to vaccines.