Development of a novel platform for CD8+ T cell antigen discovery

Recognition of specific antigens by T cells is essential for initiating an efficient adaptive immune response to eliminate threats — such as tumors and pathogens. This process has been harnessed for therapeutic purposes, leading to the development of vaccines and cellular-based treatments against cancer. Currently, identification of clinically relevant antigen—T cell receptor (TCR) interactions is possible by screening libraries of peptides and immunoreceptors, but still requires foreknowledge of one of the two counterparts. This thesis focuses on the early development stages of a novel cell-based platform for CD8+ T cell antigen discovery. The proposed method exploits engineered antigen presenting cells (APCs) that conditionally express an anti-CD69 membrane-bound antibody upon interaction between their peptide-major histocompatibility complex (pMHC) with its cognate TCR. Binding to CD69, expressed on the activated T cell, will then induce formation of cell doublets, which can be sorted via flow cytometry and sequenced in order to simultaneously retrieve the TCR’s and the antigen’s sequences — even when both of them are unknown. This double-regulated circuit aims to fill the technological gaps in antigen discovery approaches, allowing the development of therapies to be used against a larger spectrum of infections, autoimmune diseases and cancers.