title: Impaired interleukin (IL)-4-associated generation of CCR4-expressing T cells in neonates with hereditary allergy risk.
abstract: Reduced microbial exposure in early life may contribute to the increase of atopic diseases in 'westernized' societies but the underlying mechanisms remain elusive. The objective of this study was to examine how exposure to bacterial lipopolysaccharide (LPS) during early antigen encounter might influence the maturation of neonatal lymphoid cells, and to define possible differences in this respect between neonates with high risk of allergy due to a family history (FH(+)) and controls with no apparent hereditary risk (FH(-)). Cord blood mononuclear cells from the FH(+) or FH(-) group were stimulated with pure LPS or beta-lactoglobulin (beta-LG) in the presence of LPS. T cell expression of chemokine receptors CCR4 and CXCR3 was determined by flow cytometry and reverse transcription-polymerase chain reaction (RT-PCR). Cellular expression of interleukin (IL)-4 was analysed by quantitative RT-PCR, whereas interferon (IFN)-gamma was analysed by both quantitative RT-PCR and immunoassay. Stimulation with LPS, or beta-LG together with LPS, induced up-regulation of CCR4 (P < 0.05) and CXCR3 (P < 0.05). For CCR4, such up-regulation was related to the level of IL-4 produced by the same T cells (r(S) = 0.49, P = 0.03), while CXCR3 expression was negatively correlated with the IL-4 levels (r(S) = -0.56, P = 0.02). Compared with the FH(-) group, the FH(+) group showed a significantly lower capacity for generation of CCR4(+) T cells (mean percentage of total T cells: FH(+), 2.42%versus FH(-), 5.74%; P < 0.01), whereas induction of CXCR3 and IFN-gamma did not differ significantly between the two groups. When the immune system in early life encounters antigen together with LPS, the T cell potential for compartmentalized interaction with other immune cells might be increased by elevated CCR4- and CXCR3-expression levels. In neonates at hereditary allergy risk, this putative homeostatic mechanism could theoretically be jeopardized due to decreased up-regulation of CCR4. Conversely, Th1 responses to antigen in the presence of LPS did not appear to be reduced compared with controls.
authors.affiliation: Laboratory for Immunohistochemistry and Immunopathology, Institute of Pathology, University of Oslo, Rikshospitalet University Hospital, Oslo, Norway.
authors.forename: U
authors.initials: U
authors.lastname: Haddeland
authors.forename: G B
authors.initials: GB
authors.lastname: Sletten
authors.forename: P
authors.initials: P
authors.lastname: Brandtzaeg
authors.forename: B
authors.initials: B
authors.lastname: Nakstad
mesh_terms: D016022:Case-Control Studies; D002478:Cells, Cultured; D004781:Environmental Exposure; D005434:Flow Cytometry; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics* / Q000276:immunology; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology*; D007782:Lactoglobulins / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D054398:Receptors, CCR4; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012306:Risk; D018709:Statistics, Nonparametric; D018418:Th2 Cells / Q000276:immunology*
chemical_list: C515354:CCR4 protein, human; C515187:CXCR3 protein, human; D007782:Lactoglobulins; D008070:Lipopolysaccharides; D054398:Receptors, CCR4; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D015847:Interleukin-4; D007371:Interferon-gamma