CD4+CD25-mTGFbeta+ T cells induced by nasal application of ovalbumin transfer tolerance in a therapeutic model of asthma.
BACKGROUND
Intranasal administration of high amount of allergen was shown to induce tolerance and to reverse the allergic phenotype. However, mechanisms of tolerance induction via the mucosal route are still unclear.


OBJECTIVE
To characterize the therapeutic effects of intranasal application of ovalbumin (OVA) in a mouse model of bronchial inflammation as well as the cellular and molecular mechanisms leading to protection upon re-exposure to allergen.


METHODS
After induction of bronchial inflammation, mice were treated intranasally with OVA and re-exposed to OVA aerosols 10 days later. Bronchoalveolar lavage fluid (BALF), T cell proliferation and cytokine secretion were examined. The respective role of CD4(+)CD25(+) and CD4(+)CD25(-) T cells in the induction of tolerance was analysed.


RESULTS
Intranasal treatment with OVA drastically reduced inflammatory cell recruitment into BALF and bronchial hyperresponsiveness upon re-exposure to allergen. Both OVA- specific-proliferation of T cells, T(h)1 and T(h)2 cytokine production from lung and bronchial lymph nodes were inhibited. Transfer of CD4(+)CD25(-) T cells, which strongly expressed membrane-bound transforming growth factor β (mTGFβ), from tolerized mice protected asthmatic recipient mice from subsequent aerosol challenges. The presence of CD4(+)CD25(+)(Foxp3(+)) T cells during the process of tolerization was indispensable to CD4(+)CD25(-) T cells to acquire regulatory properties. Whereas the presence of IL-10 appeared dispensable in this model, the suppression of CD4(+)CD25(-)mTGFβ(+) T cells in transfer experiments significantly impaired the down-regulation of airways inflammation.


CONCLUSIONS
Nasal application of OVA in established asthma led to the induction of CD4(+)CD25(-)mTGFβ(+) T cells with regulatory properties, able to confer protection upon allergen re-exposure.
Division of Immunology and Allergy, Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Céline
C
Pellaton-Longaretti
Caroline
C
Boudousquié
Nathalie
N
Barbier
Catherine
C
Barbey
Constance Barazzone
CB
Argiroffo
Yves
Y
Donati
Alain
A
Sauty
François
F
Spertini
D000281:Administration, Intranasal; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000628:therapy*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D003888:Desensitization, Immunologic / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D007108:Immune Tolerance; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D008168:Lung / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D000485:Allergens; D016207:Cytokines; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta; D010047:Ovalbumin