Enhanced biophysical characteristics of HIV-specific TCRs in HIV elite controllers drive superior immune control compared to vaccines 3415

Abstract Description T cells are central to adaptive immunity, with TCR-pMHC interactions critical for initiating immune responses. Despite extensive efforts, HIV vaccines have not succeeded, partly due to vaccine-induced HIV-specific CD8+ T cells exhibit low antigen receptor sensitivity. Leveraging 2D micropipette and biomembrane force probes, we quantified the biophysical interactions of HIV-specific TCRs from elite controllers/long-term non-progressors (EC/LTNP) and vaccinee (VC) at single-molecule level. We discovered that TCRs targeting shared antigens exhibit significantly higher 2D affinity in EC/LTNP than VC, especially with CD8 engagement. TCRs from EC/LTNP also displayed pronounced catch-bond characteristics, with markedly higher peak bond lifetimes at optimal force levels. Notably, TCRs specific to protective alleles HLA-B27 and B57 exhibited stronger catch-bond behavior than TCRs targeting antigens restricted to other alleles, providing a potential biophysical mechanism for their protective roles. By demonstrating that TCR-pMHC interactions differ between EC/LTNP and VC, our study shows that TCRs from EC/LTNP are inherently more protective. Understanding the biophysical properties including catch-bond dynamics and 2D binding kinetics of the most effective TCRs in combating disease bridges critical gaps in TCR-mediated immune control and provides insights not only for improving HIV vaccine strategies but also for advancing approaches in other infectious diseases and T cell-based therapy. Topic Categories Vaccines and Immunotherapy (VAC)