Regulatory T Cell Specificity Directs Tolerance versus Allergy against Aeroantigens in Humans

Abstract

FOXP3+ regulatory T cells (Tregs) maintain tolerance against self-antigens and innocuous environmental antigens. However, it is still unknown whether Treg-mediated tolerance is antigen specific and how Treg specificity contributes to the selective loss of tolerance, as observed in human immunopathologies such as allergies. Here, we used antigen-reactive T cell enrichment to identify antigen-specific human Tregs. We demonstrate dominant Treg-mediated tolerance against particulate aeroallergens, such as pollen, house dust mites, and fungal spores. Surprisingly, we found no evidence of functional impairment of Treg responses in allergic donors. Rather, major allergenic proteins, known to rapidly dissociate from inhaled allergenic particles, have a generally reduced capability to generate Treg responses. Most strikingly, in individual allergic donors, Th2 cells and Tregs always target disparate proteins. Thus, our data highlight the importance of Treg antigen-specificity for tolerance in humans and identify antigen-specific escape from Treg control as an important mechanism enabling antigen-specific loss of tolerance in human allergy.

The Role of Vitamin D in the Immune System as a Pro-survival Molecule

“…171,[200][201][202][203][204] Allergy is finely regulated by CD4 þ CD25 þ Foxp3 þ T-reg cells, [205][206][207] but recent evidence found that this role is particularly related to the immune tolerance mechanism. 208 The role of vitamin D in immune tolerance has recently been addressed 37,119,208,209 and represents a novelty in vitamin D research. Vitamin D participates in CD4þ T-cell differentiation in the thymus, as it should be a fundamental factor able to regulate the level of thymosin-β4 in thymocytes.…”

An identical mechanism governs self-nonself discrimination and effector class regulation

“…(Levine et al, 2014), (Vahl et al, 2014). We predict that in health, antigen (epitope)-specificity of Tregs and conventional memory CD4 + T cells would be non-overlapping and mutually exclusive (Golding et al, 2017), (Bacher et al, 2016).…”

Strategies to Study T Cells and T Cell Targets in Allergic Disease

“…In the presence of allergen or whole allergen extract, allergen peptide-specific T cells will have expanded and are now present in high abundance, making them easily detectable after restimulation with single peptides. T cell reactivity I response to a peptide can be measured by a variety of assays, most commonly using proliferation, cytokine production, or upregulation of activation marker as a readout [22,36,37]. This method is extremely useful to expand very rare antigen-specific CD4+ populations.…”

“…It acts as a co-stimulatory molecule, binding to CD40 on antigen-presenting cells, which can lead to several downstream events depending on the target cell type. Several studies designed to study allergen-specific effector cells in cohorts suffering from allergy, asthma, or who have been treated with AIT have successfully applied this methodology to immunologically characterize and isolate allergen-specific T cells ex vivo [37,45]. The caveat of using CD154 as a selection marker for activated, allergen-specific T cells is that it is also typically stained intracellularly.…”