title: TLR2 agonists enhance CD8+Foxp3+ regulatory T cells and suppress Th2 immune responses during allergen immunotherapy.
abstract: Pam3CSK4, a synthetic TLR2 ligand, has been shown to expand CD4+ regulatory T cells (Treg cells). Less is known about the function of CD8+ Treg cells than about the function of CD4+ Treg cells generated during allergen-specific immunotherapy (IT). This study investigated whether Dermatophagoides pteronyssinus-specific IT could expand the CD8+CD25+Foxp3+ Treg population and whether Pam3CSK4 could enhance the Treg population. PBMCs were isolated from healthy control subjects and from mite-sensitive asthmatic patients during IT at three specific times: before IT and 6 mo and 1 y after the maximum-tolerated dose. This study was performed without a placebo-controlled group. D. pteronyssinus-specific IT induced a significant increase in CD8+Foxp3+ Treg cells expressing intracellular IL-10 and granzyme B. Costimulation of PBMCs with Pam3CSK4 and D. pteronyssinus 2 expanded the CD8+CD25+Foxp3+ Treg population and inhibited D. pteronyssinus 2-induced IL-4 production. Pam3CSK4-treated CD8+CD25+ Treg cells directly suppressed CD4+ T cell proliferation by cell-contact inhibition. TUNEL revealed that CD8+CD25+ Treg cells, but not CD4+CD25+ Treg cells, directly induced CD4+CD45ROhi+ apoptosis. Our results provide direct evidence that Pam3CSK4 induces an immunomodulatory effect by inducing CD8+ Treg cells; therefore, it may be a good adjuvant for the treatment of mite allergies.
authors.affiliation: Department of Pediatrics, Changhua Christian Hospital and Institute of Clinical Medicine, National Ynag-Ming University, Taipei, Taiwan, Republic of China.
authors.forename: Yi-Giien
authors.initials: YG
authors.lastname: Tsai
authors.forename: Kuender D
authors.initials: KD
authors.lastname: Yang
authors.forename: Dau-Ming
authors.initials: DM
authors.lastname: Niu
authors.forename: Jien-Wen
authors.initials: JW
authors.lastname: Chien
authors.forename: Ching-Yuang
authors.initials: CY
authors.lastname: Lin
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000293:Adolescent; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002469:Cell Separation; D002648:Child; D002675:Child, Preschool; D003888:Desensitization, Immunologic / Q000379:methods*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D006967:Hypersensitivity / Q000517:prevention & control; D055666:Lipopeptides / Q000627:therapeutic use*; D008297:Male; D039981:Pyroglyphidae; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D039741:Antigens, Dermatophagoides; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2