Impaired calcium influx underlies skewed T helper cell differentiation in children with IgE-mediated food allergies

C L Lai; B Santner-Nanan; P J Maltese; C K S Ong; D J Palmer; D E Campbell; M Makrides; M Gold; R Nanan; S L Prescott; P S Hsu

doi:10.1111/all.16310

Impaired calcium influx underlies skewed T helper cell differentiation in children with IgE-mediated food allergies

Allergy. 2024 Sep 9. doi: 10.1111/all.16310. Online ahead of print.

Authors

C L Lai^{1

2

3

4}, B Santner-Nanan⁵, P J Maltese^{2

3}, C K S Ong^{2

3}, D J Palmer^{4

6

7}, D E Campbell^{3

4}, M Makrides^{8

9}, M Gold¹⁰, R Nanan⁵, S L Prescott^{7

11

12}, P S Hsu^{1

2

3

4}

Affiliations

¹ Department of Allergy and Immunology, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
² Kids Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
³ Discipline of Child and Adolescent Health, The University of Sydney, Sydney, New South Wales, Australia.
⁴ Centre for Food Allergy Research (CFAR), Murdoch Children's Research Institute, Parkville, Victoria, Australia.
⁵ Sydney Medical School Nepean and Charles Perkins Centre Nepean, The University of Sydney, Kingswood, New South Wales, Australia.
⁶ Telethon Kids Institute, The University of Western Australia, Nedlands, Western Australia, Australia.
⁷ School of Medicine, The University of Western Australia, Crawley, Western Australia, Australia.
⁸ South Australian Health and Medical Research Institute, SAHMRI Women and Kids, Adelaide, South Australia, Australia.
⁹ School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia.
¹⁰ Discipline of Paediatrics, School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia.
¹¹ The ORIGINS Project, Telethon Kids Institute, The University of Western Australia, Perth Children's Hospital, Nedlands, Western Australia, Australia.
¹² Nova Institute for Health, Baltimore, Maryland, USA.

PMID: 39250135
DOI: 10.1111/all.16310

Abstract

Background: Reasons for Th2 skewing in IgE-mediated food allergies remains unclear. Clinical observations suggest impaired T cell activation may drive Th2 responses evidenced by increased atopic manifestations in liver transplant patients on tacrolimus (a calcineurin inhibitor). We aimed to assess differentiation potential, T cell activation and calcium influx of naïve CD4⁺ T cells in children with IgE-mediated food allergies.

Methods: Peripheral blood mononuclear cells from infants in the Starting Time for Egg Protein (STEP) Trial were analyzed by flow cytometry to assess Th1/Th2/Treg development. Naïve CD4⁺ T cells from children with and without food allergies were stimulated for 7 days to assess Th1/Th2/Treg transcriptional factors and cytokines. Store operated calcium entry (SOCE) was measured in children with and without food allergies. The effect of tacrolimus on CD4⁺ T cell differentiation was assessed by treating stimulated naïve CD4⁺ T cells from healthy volunteers with tacrolimus for 7 days.

Results: Egg allergic infants had impaired development of IFNγ⁺ Th1 cells and FoxP3⁺ transitional CD4⁺ T cells compared with non-allergic infants. This parallels reduced T-bet, IFNγ and FoxP3 expression in naïve CD4⁺ T cells from food allergic children after in vitro culture. SOCE of naïve CD4⁺ T cells was impaired in food allergic children. Naïve CD4⁺ T cells treated with tacrolimus had reduced IFNγ, T-bet, and FoxP3, but preserved IL-4 expression.

Conclusions: In children with IgE-mediated food allergies, dysregulation of T helper cell development is associated with impaired SOCE, which underlies an intrinsic impairment in Th1 and Treg differentiation. Along with tacrolimus-induced Th2 skewing, this highlights an important role of SOCE/calcineurin pathway in T helper cell differentiation.

Keywords: IgE‐mediated food allergy; helper T cells; naïve CD4 T cells; regulatory T cell; store operated calcium entry (SOCE).

Abstract

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