This work was supported by grant (SR/SO/BB/0037/2011) from DST, India. NM is supported by a Senior Research Ganetespib molecular weight Fellowship from CSIR, India. “
“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 Dasatinib 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. In contrast to traditional vaccines based on attenuated or inactivated pathogens that are often sufficiently immunogenic without added adjuvants, safer protein-based vaccines require adjuvants to induce a protective and long-lasting immune response. Antigen (Ag)-specific CD4 T helper cells play an essential role in the generation and maintenance of long-lasting humoral and cellular immunity and are therefore important vaccine targets.1,2 Successful priming and expansion of CD4 T-cell responses require T-cell Casein kinase 1 receptor (TCR) recognition of foreign peptides bound to class II major histocompatibility
complex (pMHCII) on the surface of dendritic cells (DCs). As a result of the random rearrangement and imprecise joining of the V, D and J gene segments in the α- and β-chains of the TCR, an estimated 107–108 unique TCRs are present in the pre-immune repertoire.3 Most of the variation in each chain lies in the complementary-determining region 3 (CDR3), which is encoded by the V(D)J junction and interacts with the antigenic peptide presented by the MHC class II molecule.4 Ag-specific CD4 T cells are selected from this vast pool of TCRs based on the affinity of their TCR for foreign pMHCII.5 Adjuvants are usually thought of as substances that can enhance the magnitude of Ag-specific CD4 T-cell responses and bias CD4 T-cell differentiation towards T helper type 1 (Th1) and cellular immunity.6 The scope of this review was to provide an overview of the literature indicating that adjuvants can also affect the fine specificity and clonotypic diversity of the Ag-specific CD4 T-cell responses, and to discuss the possible mechanisms involved.