Tracking Antigen-Specific T-Cells during Clinical Tolerance Induction in Humans

Abstract

Allergen immunotherapy presents an opportunity to define mechanisms of induction of clinical tolerance in humans. Significant progress has been made in our understanding of changes in T cell responses during immunotherapy, but existing work has largely been based on functional T cell assays. HLA-peptide-tetrameric complexes allow the tracking of antigen-specific T-cell populations based on the presence of specific T-cell receptors and when combined with functional assays allow a closer assessment of the potential roles of T-cell anergy and clonotype evolution. We sought to develop tools to facilitate tracking of antigen-specific T-cell populations during wasp-venom immunotherapy in people with wasp-venom allergy. We first defined dominant immunogenic regions within Ves v 5, a constituent of wasp venom that is known to represent a target antigen for T-cells. We next identified HLA-DRB1*1501 restricted epitopes and used HLA class II tetrameric complexes alongside cytokine responses to Ves v 5 to track T-cell responses during immunotherapy. In contrast to previous reports, we show that there was a significant initial induction of IL-4 producing antigen-specific T-cells within the first 3–5 weeks of immunotherapy which was followed by reduction of circulating effector antigen-specific T-cells despite escalation of wasp-venom dosage. However, there was sustained induction of IL-10-producing and FOXP3 positive antigen-specific T cells. We observed that these IL-10 producing cells could share a common precursor with IL-4-producing T cells specific for the same epitope. Clinical tolerance induction in humans is associated with dynamic changes in frequencies of antigen-specific T-cells, with a marked loss of IL-4-producing T-cells and the acquisition of IL-10-producing and FOXP3-positive antigen-specific CD4+ T-cells that can derive from a common shared precursor to pre-treatment effector T-cells. The development of new approaches to track antigen specific T-cell responses during immunotherapy can provide novel insights into mechanisms of tolerance induction in humans and identify new potential treatment targets.

Successful immunotherapy induces previously unidentified allergen-specific CD4+ T-cell subsets

“…Gene-expression profiling allowed the phenotypic categorization of particular CD4+ T-cell clusters, including cluster 5, which exhibited increased IL-10, CD25, and FOXP3 expression, features associated with Tregs (27,28), cluster 4, with increased IL-4 and IL-13 and low CD27, features linked to allergic Th2 cells (2), cluster 6, with low CD28 and K i -67, features linked to anergic T cells (29), cluster 3, with high CD27 and low IL-4 and IL-13 expression, features linked to nonallergic cells (2), and cluster 2, with increased IFN-γ, a feature linked to Th1 cells (30) (Fig. 2 B and C, Table 2, and Fig.…”

Current Issues on Immunotherapy in Children

“…IgG4 blocks the interaction of IgE and allergens as well as the presentation of allergen to T cells. In the late phase, after one to several months, the immune response from Th2 to Th1 is reoriented, as well as the increase in the number and function of both types of T-regulatory cells (T-reg): natural (nT-reg) and inducible (iT-reg) [107]. iT-reg originated from naive CD4 + T lymphocytes and they are the most important source of IL-10, which is an important factor in peripheral tolerance [108,109], because it inhibits IgE production from one, and on the other hand stimulates IgG4 secretion and in this way directly inhibits the activity of allergen-specific T lymphocytes (Forkhead box protein 3)) are thymus origin and exhibit synergistic effects with iT-reg cells [111] exposing high levels of IL-10 and TGF-beta [112].…”

Novel developments in the mechanisms of immune tolerance to allergens

“…24,31 Both subsets, thymic selected CD4 + CD25 + Tregs and inducible Tr1 cells, seem to play together in the development of tolerance under subcutaneous and sublingual SIT: [32][33][34] Studies demonstrated an increase of CD4 + CD25 + FOXP3 + and IL-10-producing Tr1 cells in nasal and oral mucosa and in the periphery during SIT as well as an association of CD4 + CD25 + with clinical efficiency. [35][36][37][38] Hypo-proliferation of PBMCs to allergens after SIT has been mainly attributed to the induction of T-regulatory cells.…”