HLA-E-restricted SARS-CoV-2 epitopes drive CD8+T cell memory in convalescent and vaccinated individuals: implications for the design of next-generation vaccines and Immunotherapeutics

uman leukocyte antigen-E (HLA-E) is a non-polymorphic, non-classical HLA class I molecule that presents signal peptides from classical HLA class Ia molecules to natural killer (NK) cell receptors.Emerging evidence suggests that HLA-E also presents viral peptides to CD8 + T cells, potentially influencing the control of viral infections.However, CD8 + T cell responses to viral epitopes presented by HLA-E remain largely unexplored.This study investigates the potential of SARS-CoV-2-derived peptides presented by HLA-E to elicit CD8 + T cell responses and to identify T cell-mediated immunity in SARS-CoV-2 infection.We describe seven peptides from SARS-CoV-2 that display substantial conservation among the predominant strains from December 2021 to February 2025.These peptides fit within the HLA-E pocket and elicit HLA-E-restricted CD8 + T cell responses by producing cytokines.HLA-E/SARS-CoV-2-restricted CD8 + T cells were identified in the blood of convalescent patients, predominantly expressing TNF-α, with lower levels of IFN-γ and IL-2, in response to predicted immunogenic epitopes.These cytokines were detected at higher frequencies in convalescent patients but were nearly absent in hospitalized patients with severe COVID-19.HLA-E/SARS-CoV-2-restricted CD8 + T cells were induced after BNT162b2 mRNA vaccination, with their frequencies increasing with more vaccine doses.Furthermore, they were significantly elicited in vaccinated individuals after SARS-CoV-2 infection.Conserved immunogenic peptides from SARS-CoV-2 can activate HLA-E-restricted T cells, suggesting their potential as universal targets for enhancing T cell-mediated immunity in controlling infection. Ht the end of this thesis, I am compelled to dedicate a few lines to the people who have accompanied me throughout this educational, scientific, professional, and, above all, human journey.This thesis would not have been possible without the support, patience, experience, and expertise of many people.