Allergen‐specific immunotherapy enhances CD8+ CD25+ CD137+ regulatory T cells and decreases nasal nitric oxide

• Published in: Pediatric allergy and immunology Vol. 30; no. 5; pp. 531 - 539
• Main Authors: Tsai, Yi‐Giien, Yang, Kuender D., Wen, Yung‐Sung, Hung, Chih‐Hsing, Chien, Jien‐Wen, Lin, Ching‐Yuang, Kalaycı, Ömer
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.08.2019
• Subjects: Adjuvants, Immunologic - pharmacology; Adolescent; Allergens; Allergic rhinitis; Allergies; allergy; Animals; Antigens, Dermatophagoides - immunology; CD137; CD137 antigen; CD25 antigen; CD4 antigen; CD8 antigen; CD8 Antigens - metabolism; Cell Proliferation; Cells, Cultured; Child; Contact inhibition; Dermatophagoides pteronyssinus - immunology; Desensitization, Immunologic - methods; Enzyme-linked immunosorbent assay; Epithelial cells; Female; Flow cytometry; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Foxp3 protein; Humans; Hypersensitivity; Hypersensitivity - immunology; Hypersensitivity - therapy; Immunoregulation; Immunotherapy; Inflammation; Interleukin-2 Receptor alpha Subunit - metabolism; Lipopeptides - pharmacology; Lymphocytes; Lymphocytes T; Male; Mucosa; Nitric oxide; Nitric Oxide - analysis; Nitric-oxide synthase; Nose; regulatory T cells; RNA, Small Interfering - genetics; T-Lymphocytes, Regulatory - immunology; TLR2 protein; Toll-Like Receptor 2 - agonists; Toll-like receptors; Toll‐like receptor 2; Tumor Necrosis Factor Receptor Superfamily, Member 9 - genetics; Tumor Necrosis Factor Receptor Superfamily, Member 9 - metabolism; Tumor necrosis factor receptors; Western blotting; regulatory T cells; allergy; CD137; Toll-like receptor 2; immunotherapy
• ISSN: 0905-6157; 1399-3038; 1399-3038
• DOI: 10.1111/pai.13061

Background 4‐1BB (CD137), a member of the inducible tumor necrosis factor receptor (TNFR) family, is expressed on regulatory T (Treg) cells and regulates Treg cells to control allergic inflammation. Pam3CSK4, a synthetic TLR2 ligand that can expand CD8+ Treg function, is a promising adjuvant for allergen immunotherapy (IT). We examined whether Dermatophagoides pteronyssinus (Der p) IT and Pam3CSK4 could enhance CD8+ CD25+ CD137+ Treg suppressive function to decrease nasal nitric oxide (nNO) levels. Methods Nasal symptom scores, nNO levels, PBMCs, and inferior turbinate biopsies were obtained from 40 mite‐sensitive perennial allergic rhinitis (PAR) patients before and after one year of Der p IT and 30 non‐allergic control subjects. CD137 expression on CD8+ CD25+ T cells and suppressive function of CD8+ CD25+ CD137+ Tregs was measured using flow cytometry. Cytokine levels were analyzed by ELISA. Inducible nitric oxide synthase production by nasal epithelial cells after co‐culturing with CD8+ CD25+ CD137+ T cells was analyzed by Western blotting. Results Der p IT improved nasal symptom scores, decreased nNO levels, and increased CD137 expression on CD8+ T cells in PBMCs and nasal mucosa. Pam3CSK4 expanded the CD8+ CD25+ CD137+ population in PBMCs. Pam3CSK4‐stimulated CD8+ CD25+ CD137+ Tregs induced IL‐10 and TGF‐β and suppressed CD4+ CD25‐ T‐cell proliferation mainly by cell contact inhibition. CD8+ CD25+ CD137+ Tregs cultured with nasal epithelial cells suppressed Der p 2–induced iNOS production. Silencing CD137 in sorted CD8+ CD25+ T cells decreased Pam3CSK4‐activated Foxp3 expression. Conclusion Der p IT expanded CD8+ CD25+ CD137+ Tregs and decreased nNO levels. Induced CD137 expression on CD8+ CD25+ Tregs by Pam3CSK4 stimulation may help suppress allergic inflammation during IT.