Abstract
Background: 4‐1BB (CD137), a member of the inducible tumor necrosis factor recep‐
tor (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 ex‐
amined whether Dermatophagoides pteronyssinus (Der p) IT and Pam3CSK4 could en‐
hance CD8+ CD25+ CD137+ Treg suppressive function to decrease nasal nitric oxide
(nNO) levels.
Methods: Nasal symptom scores, nNO levels, PBMCs, and inferior turbinate biop‐
sies 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 in‐
creased 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 lev‐
els. Induced CD137 expression on CD8+ CD25+ Tregs by Pam3CSK4 stimulation may
help suppress allergic inflammation during IT.
