Regulation of CD4 T-cell receptor diversity by vaccine adjuvants

Abstract

New vaccines based on soluble recombinant antigens (Ags) require adjuvants to elicit long-lasting protective humoral and cellular immunity. Despite the importance of CD4 T helper cells for the generation of long-lived memory B and CD8 T cells, the impact of adjuvants on CD4 T-cell responses is still poorly understood. Adjuvants are known to promote dendritic cell (DC) maturation and migration to secondary lymphoid organs where they present foreign peptides bound to class II major histocompatibility complex molecules (pMHCII) to naïve CD4 T cells. Random and imprecise rearrangements of genetic elements during thymic development ensure that a vast amount of T-cell receptors (TCRs) are present in the naïve CD4 T-cell repertoire. Ag-specific CD4 T cells are selected from this vast pre-immune repertoire based on the affinity of their TCR for pMHCII. Here, we review the evidence demonstrating a link between the adjuvant and the specificity and clonotypic diversity of the CD4 T-cell response, and consider the potential mechanisms at play.

Figure 1

Impact of adjuvants and the stability of peptides bound to class major histocompatibility complex molecules (pMHCII) antigen (Ag)-specific CD4 T-cell repertoires. (a) Dispersible adjuvants such as monophosphoryl Lipid A (MPL)-based emulsion or saline buffer containing CpG oligodeoxynucleotides focus the pigeon cytochrome c (PCC)-specific CD4 T-cell response towards high-affinity clonotypes expressing a public Vβ3-Jβ1.2 rearrangement (SLNNANSDY or 5C.C7β), whereas depot-forming adjuvants [Alum, incomplete Freund’s adjuvant (IFA) or complete Freund’s adjuvant (CFA)] expand more diverse PCC-specific CD4 T-cell repertoires characterized by the higher prevalence of low-affinity clonotypes expressing Vβ3-Jβ2.5 rearrangements. (b) Upon immunization with MPL-based emulsion, cytochrome c peptides forming low-stability pMHCII complexes with MHCII skew Ag-specific CD4 T-cell repertoires towards high-affinity clonotypes expressing the 5C.C7β chain, while altered peptide ligands forming complexes of higher stability expand more diverse and lower-affinity Ag-specific CD4 T-cell repertoires.

Figure 2

Models of adjuvant control of the CD4 T-cell immune repertoire. (a) Based on the models suggested by Medzhitov and colleagues, adjuvants with different abilities to deliver Toll-like receptor (TLR) agonists and antigen (Ag) to the same phagosomes will elicit different levels of peptides bound to class II major histocompatibility complex (pMHCII) and select CD4 T cells with different T-cell receptor (TCR) affinity. (b) Adjuvants mediate the release of a variety of inflammatory cytokines that can modulate the activity of lysosomal proteases (cathepsins) and DM molecules, altering both the level and nature of pMHCII presented. (c) Adjuvants regulate the nature and levels of costimulatory molecules (Signal 2) expressed by antigen-presenting cells (APCs), thereby modulating the strength of the TCR signal derived from pMHCII (Signal 1) and the TCR-based selection. (d) Depot-forming and dispersible adjuvants target APCs with different Ag processing and stimulatory capacities, leading to the selection of different TCR repertoires. (e) Chemical and conformational changes in pMHCII are recognized by distinct CD4 T cells.