Designing unconventional peptide modifications to universally enhance CD4+ T-cell activation (360G-Wellcome-209213_Z_17_Z)

The CD4+ T-cell response is of fundamental importance in generating effective immunity to pathogens and cancer. The interaction of the CD4+ T-cell receptor (TCR) with peptide presented by HLA class II heterodimers (pHLA-II) is the central point of the adaptive immune response. Overwhelming evidence suggests the affinity of this interaction dictates the efficacy of T-cell activation (Panhuys et al Immunity 2014), and indeed, the fundamental importance of TCR:pHLA-II affinity was illustrated in a cohort of long term HIV controllers (Benati et al JCI 2016). Crucially, low affinity TCR:pMHC interactions contribute significantly to cancer vaccine failures. The biology of this interaction has been ignored by the vast majority of vaccine studies. This project takes a fundamentally different approach to therapeutic and prophylactic vaccines, by focusing on the details of the TCR:pMHC-II interaction. We aim to utilise our proven ability to generate high affinity TCR:pMHC-II interactions, with no loss of specificity, by targeting changes in the epitope flanking regions. This approach will illustrate how HLA-bespoke vaccines can be generated, and will be tested (using HLA-DR-transgenic mouse) in models of infection and cancer. The long term aim is to match superior vaccines to the individuals' HLA background, personalising treatment, and transforming vaccine design.