Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells

doi:10.1016/j.jaci.2009.01.056

Journal of Allergy and Clinical Immunology

Volume 123, Issue 4, April 2009, Pages 774-782.e5

https://doi.org/10.1016/j.jaci.2009.01.056 Get rights and content

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_H2-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_H2/T_H1/T_H17 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_H2 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_H1/T_H2 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_H2 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.

Section snippets

Study population

We recruited pregnant mothers in an obstetric clinic in rural southern Germany in the frame of a birth cohort study (PAULCHEN). The population is representative of the subjects involved in previous farm studies.1, 3 Study enrollment through trained midwives occurred from July 2005 to September 2007 in the last trimester of pregnancy. Inclusion criteria comprised healthy neonates and mothers with uncomplicated pregnancies. Exclusion criteria included preterm deliveries, perinatal infections,

Population characteristics

Table I shows the characteristics of 82 included subjects (22 neonates of farming mothers and 60 of nonfarming mothers). Farming mothers smoked less and showed a trend toward less education compared with nonfarming mothers (P = .04 and .06, respectively). Both factors were tested for potential confounding but were revealed not to be confounders. Maternal atopy was less in farming mothers, although not significantly.

Treg cell numbers are quantitatively and qualitatively increased in cord blood of farming mothers

We assessed Treg cells by measuring the surface expression of CD4⁺CD25^high T

Discussion

This study suggests a mechanism by which the protective effect of farming exposure in pregnancy might influence neonatal immune development and subsequently reduce the development of allergic diseases. Treg cells, comprehensively assessed in number, gene expression, epigenetic regulation, and function, were mainly at higher levels and more efficient in offspring of farming compared with nonfarming mothers after specific stimulation. This was associated with decreased T_H2 cytokine levels and

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: Supported by Stiftung OMNIBUS, Friedrich-Baur Institut, Münchner Universitätsgesellschaft, Bayerische Forschungsstiftung (PIZ-140-08) (B.S.), and DFG SFB650 (J.H.).

: Disclosure of potential conflict of interest: S. Olek is an employee and stockholder of Epiontis. The rest of the authors have declared that they have no conflict of interest.

^∗: These authors contributed equally to this work.

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Reviews and feature articleMaternal farm exposure modulates neonatal immune mechanisms through regulatory T cells

Background

Objective

Methods

Results

Conclusions

Section snippets

Study population

Population characteristics

Treg cell numbers are quantitatively and qualitatively increased in cord blood of farming mothers

Discussion

Immunol Allergy Clin North Am

J Allergy Clin Immunol

Lancet

Exp Hematol

Immunity

Lancet

J Allergy Clin Immunol

Immunity

J Allergy Clin Immunol

J Invest Dermatol

Environmental exposure to endotoxin and its relation to asthma in school-age children

N Engl J Med

Toll-like receptor 4 or 2 agonists decrease allergic inflammation

Am J Respir Cell Mol Biol

Regulatory T cells as potential immunotherapy in allergy

Curr Opin Allergy Clin Immunol

Foxp3-dependent programme of regulatory T-cell differentiation

Nature

Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance

Nat Immunol

CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells

J Exp Med

Reviews and feature article
Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells