Roles of type 1 regulatory T (Tr1) cells in allergen-specific immunotherapy

Abstract

Allergen-specific immunotherapy (AIT) is the only causative treatment for allergic diseases by modification of the immune response to allergens. A key feature of AIT is to induce immunotolerance to allergens by generating antigen-specific regulatory T (Treg) cells in allergic patients. Type 1 regulatory T (Tr1) cells and forkhead box protein 3 (Foxp3)-expressing Treg cells are well known among Treg cell subsets. Foxp3 was identified as a master transcription factor of Treg cells, and its expression is necessary for their suppressive activity. In contrast to Foxp3+ Treg cells, the master transcription factor of Tr1 cells has not been elucidated. Nevertheless, Tr1 cells are generally considered as a distinct subset of Treg cells induced in the periphery during antigen exposure in tolerogenic conditions and can produce large amounts of anti-inflammatory cytokines such as interleukin-10 and transforming growth factor-β, followed by down-regulation of the function of effector immune cells independently of Foxp3 expression. Since the discovery of Tr1 cells more than 20 years ago, research on Tr1 cells has expanded our understanding of the mechanism of AIT. Although the direct precursors and true identity of these cells continues to be disputed, we and others have demonstrated that Tr1 cells are induced in the periphery by AIT, and the induced cells are re-activated by antigens, followed by suppression of allergic symptoms. In this review, we discuss the immune mechanisms for the induction of Tr1 cells by AIT and the immune-suppressive roles of Tr1 cells in AIT.

The Role of Regulatory T Cells in Allergic Diseases: Collegium Internationale Allergologicum (CIA) Update 2024

“…IL-10 is crucial for effector T cell anergy and for allergen-specific IgG production [196]. The percentages of IL-10-producing CD49b + LAG-3 + Tr1 cells in allergic patients are significantly lower than in healthy subjects [97], which significantly increase after successful AIT [197]. It was suggested that the IL-10-related transcription factor E4BP4 plays a regulatory role, as its mRNA and the numbers of Tr1 cells were elevated in blood of patients treated with SCIT [198].…”

Regulatory T Cell-Targeted Immunomodulatory Therapy for Long-Term Clinical Improvement of Atopic Dermatitis: Hypotheses and Perspectives

“…ACT with Treg cells can be achieved using three methods: polyclonal Treg cells without antigen stimulation, antigen-stimulated and expanded Treg cells, and Treg cells with a genetically engineered chimeric antigen receptor. Adoptive transfer of Treg cells has been proposed to treat T cell-mediated immune diseases including organ transplant rejection, autoimmune diseases, and allergic diseases [ 134 , 135 ]. However, human clinical studies using the adoptive transfer of ex vivo expanded Treg cells for AD or other allergic diseases have not been conducted.…”

Mechanism underlying polyvalent IgG-induced regulatory T cell activation and its clinical application: Anti-idiotypic regulatory T cell theory for immune tolerance

“…Activated Treg cells release IL-10 and suppress Th2 cell-mediated allergic inflammation. However, there are still controversies regarding the main subpopulation of Treg cells mediating therapeutic effects involved in allergen immunotherapy (CD4 + Foxp3 + Treg cells and/or CD4 + Foxp3 - IL-10 + Treg cells) ( 91 ).…”

“…Expansion of CD4 + Foxp3 + Treg cells in the peripheral blood has been reported in patients with autoimmune diseases after intravenous administration of high-dose (1~2 g/Kg of body weight) heterologous IVIg ( 60 , 65 , 93 ). Continuous regular intravenous infusion of a high dose of polyvalent human IgG is needed to achieve a long-term clinical improvement in patients with autoimmune diseases ( 60 , 91 , 93 ). This requirement of continuous treatment has been attributed to the low concentration and low affinity of natural anti-idiotype antibodies to pathogenic autoantibodies contained in IVIg ( 17 ).…”