Molecular mechanisms in neonatal naive CD4+ T cells contributing to the reduced Th1 immune response in human neonates
- Human neonates are highly susceptible to infection by intracellular pathogens compared to adults, due in large part to a reduction in CD4+ T cell-mediated T helper type 1 (Th1) immunity. We have investigated the molecular mechanisms in the neonatal naive CD4+ T cell response that contribute to this reduction in neonatal Th1 immunity, and have identified differences in gene expression, epigenetic regulation, and T cell receptor signaling between neonatal an adult naive CD4+ T cells. Significantly, neonatal naive CD4+ T cells flux calcium to a higher degree than do adult naive CD4+ T cells in response to CD3 engagement. This enhanced calcium signaling is mediated by higher levels of the microRNA miR-181a, and is not accompanied by an increase in response to CD28-mediated costimulation. In neonatal cells, an increase in calcium signaling relative to a lack of induction of the AP-1 transcription factor indicates that neonatal naive CD4+ T cells may be prone to an anergic response. Neonatal naive CD4+ T cells share an enhanced calcium response with adult CD4+ recent thymic emigrants, a less mature peripheral CD4+ T cell population. We have also confirmed decreased capacity of neonatal naive CD4+ T cells to produce the prototypic Th1 cytokine interferon-gamma (IFN-[gamma]), and have obtained evidence that epigenetic modifications mediated by de novo methyltransferase 3a (Dnmt3a) are responsible for impaired cytokine production. Comprehensive profiling of gene expression and microRNA expression have uncovered further support for our functional observations of increased calcium flux and reduced Th1 function in neonatal naive CD4+ T cells. We have found that neonatal naive CD4+ T cells have reduced Th1 function and have enhanced T cell receptor proximal signaling in the absence of an enhanced response to costimulation, constituting a unique T cell phenotype.
|Type of resource
|electronic; electronic resource; remote
|1 online resource.
|Palin, Amy Colleen
|Stanford University, Department of Immunology.
|Contag, Christopher H
|Contag, Christopher H
|Statement of responsibility
|Amy Colleen Palin.
|Submitted to the Department of Immunology.
|Ph.D. Stanford University 2012
- © 2012 by Amy Colleen Palin
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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