34 The magnitude and quality of the inflammatory cytokine response depends upon the TLR agonists35 and adjuvant vehicles used.11 Chain and colleagues have shown that exposure of DCs
to interleukin (IL)-6 dramatically altered the specificity of the T-cell response to native hen egg lysozyme (HEL) and enabled the processing and presentation of HEL cryptic T-cell epitopes.36 IL-6 was shown to modulate endosomal and lysosomal pH,36 thereby affecting the activity of lysosomal enzymes (cathepsins) involved in protein Ag degradation.37 IL-6 can also impact DM levels,37 a critical cofactor in endosomal peptide loading of MHC class II molecules that favours the presentation of peptides that possess high-stability interactions with MHC class II molecules.22 In addition to IL-6, Maurer and colleagues have shown that other proinflammatory cytokines, such as tumour necrosis INCB018424 mw factor-α (TNF-α), IL-1β this website and the anti-inflammatory cytokine, IL-10, can modulate lysosomal protease activity in DCs and affect
pMHCII presentation.38 Altogether, these studies suggest that the inflammatory cytokine environment determined by the adjuvant can influence pMHCII presentation and change the TCR repertoire of the responding CD4 T cells (Fig. 2b). In addition to their capacity to alter pMHCII presentation by DCs, adjuvants can also modulate the expression level of costimulatory molecules on the surface of DCs.6 These changes in costimulatory molecule expression can either positively why or negatively impact TCR–pMHCII interactions and thus regulate CD4 T-cell clonal selection. Allison and colleagues have suggested that engagement of cytotoxic T lymphocyte antigen-4 (CTLA-4), a receptor for costimulatory molecules CD80 and CD86 on the surface of activated CD4 T cells, regulates the breadth of the CD4 T-cell response39
by selectively inhibiting the expansion of high-affinity clonotypes.40 For CD8 T cells, there is also evidence that the balance of costimulatory signals on the surface of APCs can regulate the expansion of high-avidity CD8 T cells.41–43 Hence, by modulating the costimulatory context in which pMHCII presentation occurs, adjuvants can alter the clonotypic diversity of the CD4 T-cell compartment (Fig. 2c). Our experiments indicate that adjuvants with the capacity to create Ag depot at the site of injection broadens the CD4 T-cell repertoire by propagating lower-affinity clonotypes.25 It is possible that the propagation of low-affinity clonotypes during an immune response requires pMHCII presentation by specific APCs that are targeted by depot-forming adjuvants. Several APCs, including tissue-derived DCs (Langerhans’ cells, dermal DCs), LN-resident DCs, monocyte-derived inflammatory DCs and B cells have been shown to be involved in CD4 T-cell responses to protein Ag44–48 but little is known about the impact of adjuvants on their capacity to present pMHCII.