Heterogeneity and plasticity of the CD4 T cell compartment in viral infections

Project #1: Long-lived Tfh cells
The CD4 memory compartment has been subdivided into 3 distinct subsets that have
different functions: inflammatory T effector memory (Tem), T central memory (Tcm), and tissue resident memory (Trm) cells. Whether T follicular helper (Tfh) cells that orchestrate the humoral response persist after the pathogen is cleared is controversial. We were able to show that Tfh cells are long-lived but extremely susceptible to NAD induced cell death (NICD) and therefore have previously been overlooked. Further characterization of Tfh cells revealed that folate receptor 4 (FR4) is a superior marker to CXCR5 in identifying Tfh memory cells. Surprisingly, Tfh memory cells maintain an anabolic state characterized by increased glucose uptake and mTORc1 activity yet retain full developmental plasticity. Furthermore, we identified a previously unknown functional role of Tfh memory cells in contributing to the maintenance of the humoral immune response beyond effector time points.
Project #2: GP61 variants
Upon a viral infection, naïve CD4 T cells differentiate into inflammatory T helper 1 (Th1)
cells and Tfh cells which shape the antibody response. The role of the T cell receptor (TCR) signal strength on Th1 vs Tfh cell differentiation in a viral infection model is incompletely understood. Here, we developed a new tool that allows us to address this question in both acute and chronic viral infections. We generated LCMV strains with point mutations in the GP61 epitope, which is part of the LCMV glycoprotein and is recognized by TCR transgenic SMARTA cells. In acute infections, TCR signal strength positively correlated with Th1 induction. In contrast, chronic infections preferentially induced Tfh cells with increasing TCR signal strength and led to acquisition of surface markers associated with chronic T cell stimulation. Thus, depending on the immune context, TCR signals exerts opposite effects on the Th1 versus Tfh generation.