The susceptibility of newborns to recurrent episodes of virus-induced wheezing and atopic disorders (such as asthma) has been associated with a combination of genetic and environmental factors that favor the generation of T helper 2 (Th2) cells over T helper 1 (Th1) cells. In ongoing experiments, we have discovered a governing feature of human immune system ontogeny that explains Th2 dominance in utero and that may also determine the propensity of some but not all neonates to preferentially sustain Th2-type responses after birth. Thus, the fetal immune system is derived from multi-lineage hematopoietic stem/progenitor cells (HSPCs) that give rise to tolerogenic regulatory T cells while the adult immune system is derived from distinct HSPCs that are more likely to give rise to immunoreactive T effector cells. We hypothesize that different neonates may have varying proportions of these two compartments and that those with a higher proportion of the fetal compartment may be more predisposed to sustaining Th2 responses for a longer period of time after birth. This hypothesis will be addressed in experiments of the following Specific Aims: (1) to confirm and extend previous findings that there are gene expression and functional differences that distinguish fetal and adult myeloid cells;(2) to determine whether there is inter individual variation in the admixture of fetal and adult T and/or myeloid cells in normal umbilical cord blood (UCB) samples;and (3) to determine whether skewed fetal-to-adult T and/or myeloid cell ratios in UCB are predictive of the development of viral respiratory illness and atopic disorders, e.g. asthma. These experiments should lead to a better understanding of the pathophysiology of viral respiratory illnesses and atopic disorders of childhood, and may also generate novel insights important for the diagnosis and treatment of such diseases.
Two hematopoietic stem/progenitor cells have been detected in the context of human ontogeny, one that gives rise to tolerogenic T cells in utero and another that gives rise to immunoreactive T cells after birth. The studies of this proposal address the possibility that sequential "layering" of fetal-type and adult-type T cells and myeloid cells may occur, that different children may be born with varying admixtures of the two, and that such variability may underlie susceptibility to viral respiratory infections and asthma after birth.
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