Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells.
BACKGROUND
Cross-sectional studies suggest that maternal exposure to farming decreases the risk of allergic diseases in offspring. The potential underlying immunologic mechanisms are not understood.


OBJECTIVE
We sought to assess whether maternal farm exposure activates regulatory T (Treg) cells in cord blood, exerting T(H)2-suppressive effects after microbial stimulation.


METHODS
Eighty-four pregnant mothers were recruited before delivery. Detailed questionnaires (60 nonfarming and 22 farming mothers with 2 exclusions) assessed the farming exposures. Cord blood was stimulated with the microbial stimulus peptidoglycan (Ppg), the mitogen PHA, house dust mite extracts (Der p 1), and combinations. Treg cells (CD4+CD25(high) cells; intracellular forkhead/winged-helix family transcriptional repressor p3 [FOXP3] expression, FOXP3 levels, lymphocyte activation gene 3 mRNA expression, functional studies, and DNA methylation of the FOXP3 locus), proliferation, and T(H)2/T(H)1/T(H)17 cytokines were examined.


RESULTS
Cord blood Treg cell counts (both unstimulated and PHA stimulated) were increased with maternal farming exposures and associated with higher FOXP3 (Der p 1 + Ppg stimulation) and trendwise higher lymphocyte activation gene 3 (Ppg) expression. Furthermore, Treg cell function was more efficient with farming exposure (effector cell suppression, P = .004). In parallel, T(H)2 cytokine (IL-5) levels were decreased and associated with decreased lymphoproliferation and increased IL-6 levels (Ppg stimulation, Der p 1 + Ppg stimulation, or both; P < .05). Maternal exposure to increasing numbers of farm animals and stables was discovered to exert distinct effects on Treg cells, T(H)1/T(H)2 cells, or both. Additionally, FOXP3 demethylation in offspring of mothers with farm milk exposure was increased (P = .02).


CONCLUSIONS
Farm exposures during pregnancy increase the number and function of cord blood Treg cells associated with lower T(H)2 cytokine secretion and lymphocyte proliferation on innate exposure. One fascinating speculation is that maternal farm exposure might reflect a natural model of immunotherapy, potentially including a selection of innate stimuli in addition to allergen, shaping a child's immune system at an early stage.
Department of Pulmonary and Allergy, University Children's Hospital Munich, LMU Munich, Munich, Germany. Bianca.Schaub@med.uni-muenchen.de
Bianca
B
Schaub
Jing
J
Liu
Sabine
S
Höppler
Isolde
I
Schleich
Jochen
J
Huehn
Sven
S
Olek
Georg
G
Wieczorek
Sabina
S
Illi
Erika
E
von Mutius
D000328:Adult; D000383:Agriculture; D000818:Animals; D000829:Animals, Domestic; D015331:Cohort Studies; D016207:Cytokines / Q000096:biosynthesis; D004781:Environmental Exposure; D005260:Female; D005312:Fetal Blood / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D008213:Lymphocyte Activation; D018811:Maternal Exposure; D011247:Pregnancy; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors