Human TCR Transgenic Bet v 1-Specific Th1 Cells Suppress the Effector Function of Bet v 1-Specific Th2 Cells

Abstract

Pollinosis to birch pollen is a common type I allergy in the Northern Hemisphere. Moreover, birch pollen-allergic individuals sensitized to the major birch pollen allergen Bet v 1 frequently develop allergic reactions to stone fruits, hazelnuts, and certain vegetables due to immunological cross-reactivity. The major T cell epitope Bet v 1142–153 plays an important role in cross-reactivity between the respiratory allergen Bet v 1 and its homologous food allergens. In this study, we cloned and functionally analyzed a human αβ TCR specific for the immunodominant epitope Bet v 1142–153. cDNAs encoding TCR α- and β-chains were amplified from a Bet v 1142–153-specific T cell clone, introduced into Jurkat T cells and peripheral blood T lymphocytes of allergic and nonallergic individuals, and evaluated functionally. The resulting TCR transgenic (TCRtg) T cells responded in an allergen-specific and costimulation-dependent manner to APCs either pulsed with Bet v 1142–153 peptide or coexpressing invariant chain::Bet v 1142–153 fusion proteins. TCRtg T cells responded to Bet v 1-related food and tree pollen allergens that were processed and presented by monocyte-derived dendritic cells. Bet v 1142–153-presenting but not Bet v 14–15-presenting artificial APCs coexpressing membrane-bound IL-12 polarized allergen-specific TCRtg T cells toward a Th1 phenotype, producing high levels of IFN-γ. Coculture of such Th1-polarized T cells with allergen-specific Th2-differentiated T cells significantly suppressed Th2 effector cytokine production. These data suggest that human allergen-specific TCR can transfer the fine specificity of the original T cell clone to heterologous T cells, which in turn can be instructed to modulate the effector function of the disease initiating/perpetuating allergen-specific Th2-differentiated T cells.

Lymphocyte-Based Model Systems for Allergy Research: A Historic Overview

“…These studies demonstrated that CD4 + CD25 + Treg efficiently suppress proliferation and cytokine production of Th2 cells [227,228], while other publications suggest that Th2 clones are less susceptible to nTreg-mediated suppression when compared to Th1 clones [229]. The authors' recent observation that transduction of allergen-specific TCR into peripheral blood T cells transfers allergen reactivity and fine specificity of the original clone [106,108] has also led to the development of an nTreg-based in vitro approach. For that purpose, we cotransduced FOXP3 into allergen-specific T cells to generate T cells with nTreg phenotypic and functional properties [230,231].…”

“…This has led to the characterization of several birch- and mugwort-specific TCR (Bet v 1 and Art v 1, respectively), along with novel concepts of how to use them for specific immunomodulation [106,107,108,109]. In one approach, Neunkirchner et al [108] proved that TCR tg T cells, polarized by IL-12-decorated allergen-specific APC, are potent inhibitors of Th2 effector cells. In another approach, Schmetterer et al [109] engineered allergen-specific Treg by cotransfer into T cells of allergen-specific TCR along with the master regulator of natural Treg, FOXP3.…”

“…Therefore, the authors of this review article have cloned and expressed human-relevant allergen-specific TCR [106]. This has led to the characterization of several birch- and mugwort-specific TCR (Bet v 1 and Art v 1, respectively), along with novel concepts of how to use them for specific immunomodulation [106,107,108,109]. In one approach, Neunkirchner et al [108] proved that TCR tg T cells, polarized by IL-12-decorated allergen-specific APC, are potent inhibitors of Th2 effector cells.…”

Allergen‐specific immunotherapy: from therapeutic vaccines to prophylactic approaches

“…Allergen-expressing stem cells [122][123][124] Engineered T regulatory cells [126] Engineered Th1 cells [128] E. Passive immunization…”

“…Third, viral-like particleor experimental cell-based forms of prophylaxis may be considered [125][126][127][128]. These approaches would focus on the robust induction of early T-cell tolerance so that no allergic immune response could develop.…”