Interleukin-2/antibody complex expanding Foxp3+ regulatory T cells exacerbates Th2-mediated allergic airway inflammation

Abstract

Foxp3 + regulatory CD4 + T (Treg) cells play an essential role in preventing overt immune responses against self and innocuous foreign antigens. Selective expansion of endogenous Treg cells in response to the administration of interleukin (IL)-2/antibody complex, such as the IL-2/JES6-1 complex (IL-2C) in mice, is considered an attractive therapeutic approach to various immune disorders. Here, we investigated the therapeutic potential of IL-2C in allergic airway inflammation models. IL-2C treatment ameliorated Th17-mediated airway inflammation; however, unexpectedly, IL-2C treatment exacerbated Th2-mediated allergic airway inflammation by inducing the selective expansion of Th2 cells and type-2 innate lymphoid cells. We also found that IL-2 signaling is required for the expansion of Th2 cells in lymphoproliferative disease caused by Treg cell depletion. Our data suggest that IL-2C is selectively applicable to the treatment of allergic airway diseases depending on the characteristics of airway inflammation.

Bioinformatic Analysis and Cellular Assays Identify Substance P Influencing Th17/Treg Differentiation via the MyD88 Pathway as a Potential Contributor to the Progression of Asthma and Allergic Rhinitis

“…Phenotypic induction of regulatory T cells (Tregs) is a hallmark of successful allergen immunotherapy [ 12 ]. There are two types of Treg cells: natural regulatory T lymphocytes, which exert regulatory effects mainly in a cell-to-cell contact signaling manner, and adaptive regulatory T lymphocytes (iTreg), including type I regulatory T cells (Tr1) and Th3 cells, which mainly downregulate immune responses by secreting interleukins (IL-10) and transforming growth factor- beta (TGF- β ) [ 13 ]. Th17 and Treg cells are derived from a common initial T cell population with differentiation shifted by different environments to maintain immune homeostasis by suppressing and balancing each other's differentiation functions [ 14 ].…”

Engineering a safe monoclonal anti‐human IL‐2 that is effective in a murine model of food allergy and asthma

“…These latter approaches might be useful for the treatment of allergies, autoimmune disease, and allograft rejection 47,48 . Previously, IL‐2/JES6‐1 treatment was shown to induce Treg expansion and improve multiple diseases with different pathogenic profiles, such as Th2‐driven allergic asthma 49 . In the present study, we tested the effect of IL‐2/1C6 treatment on HDM‐induced airway inflammation and wheat gliadin food allergies.…”

“…47,48 Previously, IL-2/JES6-1 treatment was shown to induce Treg expansion and improve multiple diseases with different pathogenic profiles, such as Th2-driven allergic asthma. 49 In the present study, we tested the effect of IL-2/1C6 treatment on HDM-induced airway inflammation and wheat gliadin food allergies. We observed a reduction in allergic markers, tissue damage, and inflammation in both models after IL2/1C6 treatment.…”

Regulatory T Cells, a Viable Target Against Airway Allergic Inflammatory Responses in Asthma

“…Advances in the knowledge of the functional, biophysical and structural characteristics of IL-2 have promoted the generation of IL-2 formulations, such as IL-2/anti-IL-2 mAb complexes (130). Depending on the clone of the anti-IL-2 mAb, IL-2/anti-IL-2 mAb complex exerts differential effect on the expansion of T cell subsets (131). Studies in mice revealed that IL-2/anti-IL-2 mAb complexed with S4B6 clone induces the preferential proliferation of CD8 + T cells, while the IL-2/JES6-1 complex preferentially induces the expansion of Tregs by blocking the interaction of IL-2 with IL-2Rb (CD122) and IL-2Rg (CD132), and promoting the interaction of IL-2 with IL-2Ra (CD25) (131,132).…”

“…Depending on the clone of the anti-IL-2 mAb, IL-2/anti-IL-2 mAb complex exerts differential effect on the expansion of T cell subsets (131). Studies in mice revealed that IL-2/anti-IL-2 mAb complexed with S4B6 clone induces the preferential proliferation of CD8 + T cells, while the IL-2/JES6-1 complex preferentially induces the expansion of Tregs by blocking the interaction of IL-2 with IL-2Rb (CD122) and IL-2Rg (CD132), and promoting the interaction of IL-2 with IL-2Ra (CD25) (131,132). Particularly, the IL-2/JES6-1 complexes have already manifested exciting results in terms of suppressing organ transplant rejection (133), autoimmune and inflammatory diseases in mice such as type 1 diabetes (134), dextran sodium sulfate-induced colitis (132), experimental myasthenia (135), collagen-induced arthritis (136), experimental autoimmune encephalomyelitis (133), and allergic airway disease (137).…”