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.
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