title: Synthetic bacterial lipopeptide analogs facilitate naive CD4+ T cell differentiation and enhance antigen-specific HLA-II-restricted responses.
abstract: Synthetic di- and tri-palmitoylated bacterial lipopeptide analogs (BLpA) can enhance HLA-I-restricted immune responses. Here we show that BLpA indirectly promote antigen-driven differentiation of naive CD4+ T lymphocytes in vitro, with mechanisms that require DC and are inhibited by CTLA-4/Ig. In mixed cultures of cord blood-derived PBMC and allogeneic DC, P3CSK4 lipopeptide facilitated the transition from CCR7(+)/CD45RA(+)/CD62L+ to CCR7(-)/CD45RA(-)/CD62L(dim) T cells with kinetics significantly exceeding those obtained with the unlipidated CSK4 analog. Moreover, P3CSK4 and P2CSK4, but neither the mono-palmitoylated PCSK4 analog nor the CSK4 peptide, increased the frequency of IFN-gamma-producing T cells expanded under similar conditions. Along with this, P2CSK4 and P3CSK4, but not PCSK4, restored the in vitro antigenicity of MDP-OspA, a non-immunogenic analog of Borrelia burgdorferi major outer surface lipoprotein A, and enhanced the frequency of in vitro expanded T cells specific for the tetanus toxoid (TT) and hepatitis B surface antigen (HBsAg) peptides TT(947-967) and HBsAg(19-33) and for TT. Altogether, BLpA bearing at least two ester-bonded palmitoyl side chains indirectly enhance antigen-driven CD4+ T cell differentiation. BLpA adjuvanticity is independent of covalent bonding to Ag and Ag formulation. This information may be helpful to generate more potent recombinant vaccines.
authors.affiliation: Center for Experimental Rheumatology, Dep. of Clinical Research, University Hospital, Bern, Switzerland. Elisabetta.Padovan@dkf.unibe.ch
authors.forename: Mascia
authors.initials: M
authors.lastname: Ghielmetti
authors.forename: Marianne
authors.initials: M
authors.lastname: Zwicker
authors.forename: Tanja
authors.initials: T
authors.lastname: Ghielmetti
authors.forename: Markus M
authors.initials: MM
authors.lastname: Simon
authors.forename: Peter M
authors.initials: PM
authors.lastname: Villiger
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Padovan
mesh_terms: D000276:Adjuvants, Immunologic / Q000502:physiology*; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D060908:CTLA-4 Antigen; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D007136:Immunoglobulins / Q000276:immunology; D007700:Kinetics; D008074:Lipoproteins / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D016192:Resting Phase, Cell Cycle / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D007136:Immunoglobulins; D008074:Lipoproteins; D010455:Peptides; C061108:N-palmitoyl-S-(2,3-bis(palmitoyloxy)propyl)cysteinyl-seryl-lysyl-lysyl-lysyl-lysine