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Ontogeny and function of dendritic cells in childhood

Langrish, Claire Louise; (2002) Ontogeny and function of dendritic cells in childhood. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Infections remain a major cause of morbidity and mortality in early life. The susceptibility of infants to infections may partly be due to the immaturity of the developing immune system, creating a window of vulnerability to infections at the time of disappearance of protective maternal antibodies. Antigen presentation is central to the induction of many immune responses, yet little is known of the age-related maturation or functional ontogeny of the dendritic cell (DC). The work presented in this thesis examines the phenotype, function and T cell stimulatory capacity of neonatal cord blood derived DC's, to determine their involvement within the susceptibility of neonates to infection and the deficient immune responses observed in childhood. DC's were generated in-vitro from the adherent monocytes of cord and adult peripheral blood in the presence of IL-4 and GM-CSF. Comparable immature DC phenotypes were observed with both cord and adult samples. However, upon stimulation with various maturation stimuli, the characteristic mature phenotype with increased MHC and co-stimulatory molecule surface expression observed on adult DC's, was significantly attenuated on cord DC's. Functional studies demonstrated further variations; with cord DC's displaying divergent chemokine receptor expression, persistence of endocytosis after LPS stimulation, and an inability to produce IL-12p70. Cord DC's also exhibited reduced T cell stimulatory capacity than their adult counterparts, with lower levels of IFNγ produced by allogeneic naive CD4+ T cells, suggesting that cord DC's are intrinsically pre-programmed against Th1 immune responses. In contrast to adult DC's, cord DC's also failed to form DC-DC or DC-T cell clusters, potentially due to their failure to up-regulate CD54, which was found to be a requirement for DC-DC and DC-T clustering in adults. The inability of cord DCs to respond to maturation stimuli highlights their phenotypic immaturity, with their reduced expression of MHC and co-stimulatory molecules, and inability to effectively cluster with T cells likely to limit their T cell stimulatory capacity and their ability to effectively present antigens. In-vivo, the relative immaturity of DC phenotype and function, and their deficient T cell stimulatory capacity may contribute to the susceptibility of infants and young children to infection.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Ontogeny and function of dendritic cells in childhood
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Health and environmental sciences; Ontogeny
URI: https://discovery.ucl.ac.uk/id/eprint/10107411
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