An mRNA platform to create isolated, monospecific Th1 responses

Helper T cells (CD4 T cells) are lynchpins of adaptive immune responses. Each CD4 T cell expresses a single T-cell receptor, recognizing an epitope presented by major histocompatibility complex class II (MHC-II). Due to the enormous diversity of the T-cell repertoire, it is often desirable to study a population that responds to the same epitope. Here, we devised a novel method of selective immunization to produce a robust, monospecific helper T-cell response in mice using a modular mRNA vector. The vector encodes the target epitope attached via flexible linker to MHC-II. Immunization with this mRNA selectively elicits helper T-cell responses across a range of epitopes and MHC-II alleles. These CD4 T cells show robust, polyfunctional Th1 cytokine release when evaluated ex vivo. We tested the activity of these CD4 T cells in 2 disease models: Salmonella enterica and influenza virus. In both models, these monospecific CD4 T cells influenced the course of infection, demonstrating the utility of this experimental tool, which can produce a monospecific CD4 T-cell response.