Push-pull vaccine strategy
1. Antigen optimisation: naturally occuring pathogen peptides will not be highly immunogenic (having evolved for immune escape) --> modify amino acids which contact MHC groove while preserving presented surface --> increase peptide binding affinity (immunogenicity) while stimulating T cell responses to natural peptide
2. Push: boosting quality/quantity of CD8 response
Use of cytokines: GM-CSF promotes broad range of immune responses, induces CTL response by increasing antigen presentation
IL-12 and TNF-alpha upregulate IL-12R expression (synergy with GM-CSF)
IL-15 necessary and sufficient to produce high-avidity, long-lived CTLs - can substitute for CD4 help (e.g. in HIV infection/cancer) - rescues long-term memory response which is absent in CD4 deficiency
APCs (DCs) co-transfected with antigen and IL-15 mimic CD4 help - CD4s induce IL-15 production in DCs
Use of TLR-ligands: TLR2/6-L and TLR9-L both synergise with TLR3-L, but not with each other
TLR2 and TLR9 both signal through MyD88, TLR3 signals through TRIF; synergy = unilateral crosstalk to increase IL-12 production (MyD88) but not costimulatory molecule expression (TRIF)
Combination of all 3 TLR-Ls does not further increase magnitude of CD8 response, but does increase proportion (20% --> 100%) of high-avidity CTLs - TLR2 signals through TIRAP as well as MyD88 (why can't TLR2+TLR3 alone achieve this?)
3. Pull: inactivating regulatory elements
Type II NKT cells: cross-regulate with type I NKTs (cf Th1/Th2)
NKTs often first responders in tumour immune landscape
Anti-TGFbeta (produced by type II NKTs, induces/maintains Tregs) can work as single therapy or synergise with vaccines to increase efficacy
Source: Berzofsky, Jay 2013 Vaccine. A push-pull vaccine strategy using Toll-like receptor ligands, IL-15, and blockade of negative regulation to improve the quality and quantity of T cell immune responses http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319860/pdf/nihms344093.pdf
