Genetic restriction of antigen-presentation dictates allergic sensitization and disease in humanized mice

Alina Neunkirchner,Bernhard Kratzer,Cordula Köhler,Ursula Smole,Lukas F Mager,Klaus G Schmetterer,Doris Trapin,Victoria Leb-Reichl,Edward Rosloniec,Ronald Naumann,Lukas Kenner,Beatrice Jahn-Schmid,Barbara Bohle,Rudolf Valenta,Winfried F Pickl

doi:10.1016/j.ebiom.2018.04.001

Abstract

BackgroundImmunoglobulin(Ig)E-associated allergies result from misguided immune responses against innocuous antigens. CD4+ T lymphocytes are critical for initiating and perpetuating that process, yet the crucial factors determining whether an individual becomes sensitized towards a given allergen remain largely unknown. ObjectiveTo determine the key factors for sensitization and allergy towards a given allergen. MethodsWe here created a novel human T cell receptor(TCR) and human leucocyte antigen (HLA)-DR1 (TCR-DR1) transgenic mouse model of asthma, based on the human-relevant major mugwort (Artemisia vulgaris) pollen allergen Art v 1 to examine the critical factors for sensitization and allergy upon natural allergen exposure via the airways in the absence of systemic priming and adjuvants. ResultsAcute allergen exposure led to IgE-independent airway hyperreactivity (AHR) and T helper(Th)2-prone lung inflammation in TCR-DR1, but not DR1, TCR or wildtype (WT) control mice, that was alleviated by prophylactic interleukin(IL)-2-αIL-2 mAb complex-induced expansion of Tregs. Chronic allergen exposure sensitized one third of single DR1 transgenic mice, however, without impacting on lung function. Similar treatment led to AHR and Th2-driven lung pathology in >90% of TCR-DR1 mice. Prophylactic and therapeutic expansion of Tregs with IL-2-αIL-2 mAb complexes blocked the generation and boosting of allergen-specific IgE associated with chronic allergen exposure. ConclusionsWe identify genetic restriction of allergen presentation as primary factor dictating allergic sensitization and disease against the major pollen allergen from the weed mugwort, which frequently causes sensitization and disease in humans. Furthermore, we demonstrate the importance of the balance between allergen-specific T effector and Treg cells for modulating allergic immune responses.

Highlights

Analyses of major immune cell subsets in WT, DR1, TCR and TCR-DR1 mouse lines revealed that CD3+CD4+ T cell and CD45R/B220+ B cell numbers did not differ between TCR-DR1 and WT mice in thymus, spleen or peripheral blood (PB) (Table S2)
The high-level expression of transgenic TCRs competes with endogenous TCRs for expression in developing T cells, leading to lower numbers of T cells with an endogenous TCR (Attridge and Walker, 2014). This accounts for the observed T regulatory cells (Treg) cell paucity as the frequency of T cells potentially cross-reacting with thymically presented self-peptides is diminished, which, apart from immediate negative selection, restricts their conversion into thymus-derived(t)Treg (Attridge and Walker, 2014)
We established a novel humanized mouse model to study the mechanisms of allergic sensitization and to answer the hitherto unanswered question why certain individuals develop allergy against certain allergens

Summary

Introduction

Early studies in patient populations suffering from allergy to pollen (ambrosia, birch, mugwort), animal dander (cat) and mold (Alternaria) provided evidence that allergen-specific IgE production could be MHC-restricted (Fischer et al, 1992; JahnSchmid et al, 2005; Marsh et al, 1982; Young et al, 1994) This was confirmed when T helper cell clones from allergic patients were isolated and the existence of an allergen-specific genetic restriction of the allergen-specific immune response was demonstrated. Methods: We here created a novel human T cell receptor(TCR) and human leucocyte antigen (HLA)-DR1 (TCRDR1) transgenic mouse model of asthma, based on the human-relevant major mugwort (Artemisia vulgaris) pollen allergen Art v 1 to examine the critical factors for sensitization and allergy upon natural allergen exposure via the airways in the absence of systemic priming and adjuvants. We demonstrate the importance of the balance between allergen-specific T effector and Treg cells for modulating allergic immune responses

Objectives

Methods

Results

Conclusion