High-affinity tonic TCR:self-pMHC interactions inhibit T follicular helper cell development

Abstract

Abstract T cells receive tonic signals before encountering their immunogenic antigen, but whether or not peripheral, tonic TCR:self-pMHC interactions can affect a T cell’s response to foreign antigen remains relatively unexplored. We interrogated potential T effector functions controlled by tonic signaling with the use of a transgenic TCR system composed of two distinct CD4+ T cells that recognize the same Listerolysin O epitope but lie at opposite ends of the TCR:self-pMHC affinity spectrum. Remarkably, studies revealed differences in the ability of these two cells to produce Tfh cells during a primary immune response. The cells with lower-affinity tonic TCR:self-pMHC interactions generated a significantly greater frequency and total number of Tfh cells when compared to the high-affinity cells, which directly impacted the humoral immune response. To test whether affinity for self-pMHC controls Tfh development through tonic signaling, we generated two mouse lines: Scn5a/CD4-creERT2 and H2-DMf/f/UBC-creERT2. These mouse lines allow us to temporally increase or decrease tonic signaling, respectively. Results showed decreasing tonic self-pMHC availability did not allow for the survival of cells accustomed to high-affinity tonic TCR:self-pMHC interactions; however, increasing tonic signaling in cells that normally experience low-affinity TCR:self-pMHC interactions did indeed inhibit Tfh development. Furthermore, the H2-DMf/f mouse line was additionally crossed to various cre-strains to reveal that the CD11c+ antigen presenting cell subset is responsible for tonic signaling maintenance through presentation of self-pMHC. These studies reveal critical roles tonic signaling plays in Tfh development and CD4+ T cell survival.