CD4 T-cell

responses to complex protein Ags are restricted to a limited number of determinants, a process defined as peptide immunodominance.22 Several studies indicate that peptide immunodominance can be altered by the vaccine delivery systems used. Using MalE as a model Ag, Leclerc and colleagues found that altering the vaccine-delivery systems changed the number of MalE epitopes recognized by CD4 T cells.23 Immunization with a recombinant Salmonella strain expressing MalE protein allowed the presentation of MalE CD4 T-cell epitopes that were silent after administration of selleck compound purified MalE protein Ag in CFA.23 In a recent study, Andersen and colleagues reported that altering the vaccine-delivery systems used for a tuberculosis subunit vaccine based on fusion proteins of two mycobacterial Ags – ESAT-6 and Ag85B – also changed peptide immunodominance.24 While a recombinant Ag85B/ESAT-6 protein vaccine in a liposomal adjuvant induced primarily a CD4 T-cell response directed to an immunodominant epitope located in Ag85B, an adenovirus vector expressing the same fusion protein induced a strong CD8 response predominantly targeted to an epitope located in ESAT-6. Importantly, only the adjuvanted protein vaccine Selleck Caspase inhibitor gave efficient protection against subsequent Mycobacterium tuberculosis infection.24 Altogether these studies suggest that the formulation used to deliver a protein Ag can determine the specificity of the CD4 T-cell responses and the vaccine efficacy.

Adjuvants can alter the specificity of

the CD4 T-cell response by revealing cryptic epitopes or changing peptide dominance, but can they impact the clonotypic composition of a CD4 T-cell response directed against a defined immunodominant epitope? We have recently investigated the ability of five different adjuvants [Alum, CFA, incomplete Freund’s Phospholipase D1 adjuvant (IFA), CpG oligodeoxynucleotides (TLR9 agonists) in saline buffer and MPL-based emulsion] to elicit CD4 T-cell responses against the pigeon cytochrome c (PCC) protein in B10.BR mice.25 CD4 T-cell responses to PCC are directed against a single immunodominant peptide consisting of amino acids 88–104 presented by I–Ek.26 CD4 T cells specific for this epitope predominantly express Vα11 and Vβ3 TCR variable regions with restricted CDR3 features.27,28 All five adjuvants examined promoted a PCC-specific CD4 T-cell response dominated by clones expressing restricted TCRs, but the clonotypes selected varied across the different formulations. Dispersible adjuvants using TLR agonists (CpG, MPL) focused CD4 T-cell responses towards high-affinity clonotypes expressing TCR with a marked bias toward a public Vβ3-Jβ1.2 rearrangement (SLNNANSDY or 5C.C7β chain) in their CDR3β, as depicted in Fig. 1a. By contrast, adjuvants forming Ag deposition at the site of injection (alum, IFA and CFA) selected a more diverse CD4 T-cell response that was characterized by an increased prevalence of lower affinity clonotypes expressing Vβ3-Jβ2.