The mechanisms by which immune responses to nonpathogenic environmental antigens lead to either allergy or nonharmful immunity are unknown. Single allergen-specific T cells constitute a very small fraction of the whole CD4⁺ T cell repertoire and can be isolated from the peripheral blood of humans according to their cytokine profile. Freshly purified interferon-γ–, interleukin (IL)-4–, and IL-10–producing allergen-specific CD4⁺ T cells display characteristics of T helper cell (Th)1-, Th2-, and T regulatory (Tr)1–like cells, respectively. Tr1 cells consistently represent the dominant subset specific for common environmental allergens in healthy individuals; in contrast, there is a high frequency of allergen-specific IL-4–secreting T cells in allergic individuals. Tr1 cells use multiple suppressive mechanisms, IL-10 and TGF-β as secreted cytokines, and cytotoxic T lymphocyte antigen 4 and programmed death 1 as surface molecules. Healthy and allergic individuals exhibit all three allergen-specific subsets in different proportions, indicating that a change in the dominant subset may lead to allergy development or recovery. Accordingly, blocking the suppressor activity of Tr1 cells or increasing Th2 cell frequency enhances allergen-specific Th2 cell activation ex vivo. These results indicate that the balance between allergen-specific Tr1 cells and Th2 cells may be decisive in the development of allergy.

Summary: Specific immune suppression and induction of tolerance are essential processes in the regulation and circumvention of immune defence. The balance between allergen‐specific type 1 regulatory (Tr1) cells and T helper (Th) 2 cells appears to be decisive in the development of allergy. Tr1 cells consistently represent the dominant subset specific for common environmental allergens in healthy individuals. In contrast, there is a high frequency of allergen‐specific interleukin‐4 (IL‐4)‐secreting T cells in allergic individuals. Allergen‐specific immunotherapy can induce specific Tr1 cells that abolish allergen‐induced proliferation of Th1 and Th2 cells, as well as their cytokine production. Tr1 cells utilize multiple suppressor mechanisms, such as IL‐10 and transforming growth factor‐β (TGF‐β) as secreted cytokines and various surface molecules, such as cytotoxic T‐lymphocyte antigen 4 and programmed death‐1. IL‐10 only inhibits T cells stimulated by low numbers of triggered T‐cell receptors, which depend on CD28 costimulation. IL‐10 inhibits CD28 tyrosine phosphorylation, preventing the binding of phosphatidylinositol 3‐kinase p85 and consequently inhibiting the CD28 signalling pathway. In addition, IL‐10 and TGF‐β secreted by Tr1 cells skew the antibody production from immunoglobulin E (IgE) towards the non‐inflammatory isotypes IgG4 and IgA, respectively. Induction of antigen‐specific Tr1 cells can thus re‐direct an inappropriate immune response against allergens or auto‐antigens using a broad range of suppressor mechanisms.

Despite the importance of the co-receptor PD-1 in T cell immunity, the upstream signaling pathway that regulates PD-1 expression has not been defined. Glycogen synthase kinase 3 (GSK-3, isoforms α and β) is a serine-threonine kinase implicated in cellular processes. Here, we identified GSK-3 as a key upstream kinase that regulated PD-1 expression in CD8(+) T cells. GSK-3 siRNA downregulation, or inhibition by small molecules, blocked PD-1 expression, resulting in increased CD8(+) cytotoxic T lymphocyte (CTL) function. Mechanistically, GSK-3 inactivation increased Tbx21 transcription, promoting enhanced T-bet expression and subsequent suppression of Pdcd1 (encodes PD-1) transcription in CD8(+) CTLs. Injection of GSK-3 inhibitors in mice increased in vivo CD8(+) OT-I CTL function and the clearance of murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 and reversed T cell exhaustion. Our findings identify GSK-3 as a regulator of PD-1 expression and demonstrate the applicability of GSK-3 inhibitors in the modulation of PD-1 in immunotherapy.

Objective: To evaluate the clinical outcome and changes in allergen-specific antibodies during sublingual immunotherapy (SLIT) in house dust mite (HDM)-allergic asthma patients and to compare levels of allergen-specific antibodies in HDM-allergic patients before and after treatment with that of healthy controls. Method: Thirty-one asthma patients allergic to HDM were studied. Patients in groups I (n = 17) and II (n = 14) received SLIT with a standardized Dermatophagoides pteronyssinus plus Dermatophagoides farinae 50/50 extract for 6 and 12 months, respectively. A group of healthy children (n = 8) were enrolled as controls. Patients in both groups were evaluated at the start and at the end of treatment according to daily symptom and medication scores, lung function and skin prick tests, PC20, blood eosinophil count, and Der-p-1-specific IgE, IgA, IgG1 and IgG4 levels. Results: Drug consumption decreased significantly in both groups. Furthermore, PC20 and forced expiratory flow between 25 and 75% of vital capacity of patients in group II improved significantly. Although specific IgA, IgG1 and IgG4 levels did not change throughout the treatment period, total eosinophil count and specific IgE decreased significantly in both groups. According to baseline measurements, specific IgA levels of patients in groups I and II were significantly lower than that of controls. This difference disappeared at the end of the treatment period in both groups. Conclusion: SLIT seems to be effective in ameliorating clinical symptoms, drug consumption and bronchial hyperreactivity, and results in downregulation of Der-p-1-specific IgE production. Furthermore, at the end of SLIT, specific IgA levels, which were decreased compared to healthy controls initially, did no longer differ between patients and controls.