Abstract
T lymphocytes have a crucial role in initiating and promoting type I allergies. Their responses are tightly regulated by numerous activating and inhibitory signals provided by APCs. Here we have addressed the role of the major coinhibitory receptors PD-1, CTLA-4, BTLA and LAG-3 in allergen-specific CD4+ T cell responses. PBMCs of healthy individuals and 41 patients allergic to house dust mites, birch, grass or mugwort pollen were stimulated with allergenic extracts and expression of coinhibitory receptors on responding CD4+ T cells was assessed. Blocking antibodies to PD-1, CTLA-4, BTLA and LAG-3 were used to evaluate the role of coinhibitory pathways. Allergen-specific CD4+ T cells showed strong upregulation of PD-1, LAG-3 and CTLA-4 upon stimulation, whereas BTLA was downregulated. Blockade of PD-1 strongly enhanced proliferation and cytokine production (IL-10; TH1 cytokines IFN-γ, TNF-α; TH2 cytokines IL-5, IL-13) of allergen-specific CD4+ T cells derived from allergic as well as non-allergic individuals. BTLA blockade enhanced proliferation but not cytokine production in response to house dust mite extract. Blocking LAG-3 was ineffective and surprisingly, we observed reduced proliferation and cytokine production in presence of a CTLA-4 antibody. Our results point to a unique potency of PD-1 pathways to dampen allergen-specific human T cells.
Highlights
Allergen-specific CD4+ T cells play crucial roles in type I allergy[1,2,3]
We have analyzed the expression of major immune checkpoints (CTLA-4, PD-1, BTLA and LAG-3) on T cells responding to common allergen sources
We used a previously described engineered antigen presenting cells (APC) system based on HLA-DR1+ CD80+ K562 cells expressing the single dominant epitope of the major mugwort allergen Art v 1 (Art v 125–34) targeted to the MHC class II presentation pathway via fusion to the invariant chain33. eAPC expressing the PD-1 ligand PD-L2 induced significantly lower proliferative responses in Art v 1 specific T cell clones (TCC) compared to eAPC presenting Art v 1 in absence of PD-1 ligands and the presence of a PD-1 blocking antibody reverted this effect (Fig. 1A,B)
Summary
Allergen-specific CD4+ T cells play crucial roles in type I allergy[1,2,3]. TH2 cells and IL-4 producing Tfh cells promote allergy by inducing class switching to the production of IgE in B cells recognizing allergens[4]. Studies in murine models indicate an important role of PD-1 pathways in asthma and demonstrate that PD-1 and BTLA are required for termination of acute allergic airway inflammation[30,31,32]. Taken together, these observations suggest that dysregulation of T cell inhibitory pathways can contribute to aberrant T cell responses resulting in autoimmunity and immune pathologies like IgE-mediated allergies. We have analyzed the expression of major immune checkpoints (CTLA-4, PD-1, BTLA and LAG-3) on T cells responding to common allergen sources. Our results indicate a singular role of PD-1 in dampening allergen-specific human T cells
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