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Helios-Negative Regulatory T Cells as a Key Factor of Immune Tolerance in Nonallergic Beekeepers

Ruiz-Leon B1,2,3*, Navas A1,2*, Serrano P1,2,3, Espinazo M1,3, Guler I1, Alonso C1,2,3, Jurado A1,2,3, Moreno-Aguilar C1,2,3

1Maimonides Biomedical Research Institute of Cordoba (IMIBIC)/Reina Sofia University Hospital/University of Cordoba, Cordoba, Spain
2Department of Immunology and Allergy, Reina Sofia University Hospital, Cordoba, Spain
3National Network ARADyAL. Health Institute Carlos III, Madrid, Spain
*Both authors contributed equally

J Investig Allergol Clin Immunol 2022; Vol 32(6) : 451-459
doi: 10.18176/jiaci.0722

Background: Although exposure to stings has been identified as the leading risk factor for anaphylaxis due to Hymenoptera venom allergy, professional beekeepers receive hundreds of stings yearly without developing systemic reactions.
This study aims to analyze the mechanisms underlying bee venom tolerance in beekeepers.
Methods: A cross-sectional study was conducted. Participants were recruited and classified into 3 groups: allergic patients (APs), who experienced systemic reactions after bee stings, with a positive intradermal test and specific IgE (sIgE) to Apis mellifera venom (AmV); tolerant beekeepers (TBKs), who received ≥50 stings/year; and healthy nonexposed controls (HCs). We measured serum levels of sIgE and specific IgG4 (sIgG4) to AmV, rApi m 1, rApi m 2, rApi m 3, Api m 4, rApi m 5, and rApi m10, as well as AmV-induced basophil degranulation, percentage of T-cell subsets, regulatory T cells (Treg), and IL-10 production.
 Compared with TBKs, APs had high levels of sIgE to AmV and all its allergic components (P<.001), together with a high basophil activation rate (P<.001). Conversely, compared with APs, TBKs had higher levels of sIgG4 (P<.001) and IL-10 (P<.0001), as well as an enhanced CTLA-4+ Treg population (P=.001), expanded Helios– Treg (P<.003), and reduced type 1 helper T cells (TH1) (P=.008), TH2 (P=.004), and TH17 (P=.007) subsets.
Conclusions: The profile of TBKs, which was strongly marked by Treg activity, differed from that of TBKs. This natural tolerance would be led by the expansion of inducible Helios– Treg cells at the peripheral level. The Helios– Treg population could be a novel candidate biomarker for monitoring tolerance.

Key words: Helios protein, Regulatory T cells, Immune tolerance, Bee venom allergy, Beekeeping