BCL6-dependent TCF-1+ progenitor cells maintain effector and helper CD4 T cell responses to persistent antigen

Abstract

Shortly after priming, the fate of activated CD4 T cells is segregated into BCL6+ follicular helper T (Tfh) and BCL6− effector (Teff) cells. However, it remains unknown how these subsets are sustained in the presence of chronic antigen stimulation. Using a combination of single cell- and population-based approaches, we show that in chronic viral infection, activated CD4 T cells differentiate into BCL6-dependent TCF-1+ progenitor cells with superior capacity to expand and give rise to both Teff and Tfh. They share properties with progenitor-exhausted CD8 T cells and are required for the continued generation of Teff cells as antigen persists. In response to tumors, an analogous CD4 T cell population develops in draining lymph nodes. Our study reveals the heterogeneity and plasticity of CD4 T cells upon encountering persistent antigen and highlights their population dynamics through a stable bipotent intermediate state.

Distribution-modeling quantifies collective Th cell decision circuits in chronic inflammation

“…Notably, the relapse-effects predicted by our model for a chronic inflammation scenario are commonly found in several autoimmune disorders (9). While several factors have been identified that contribute to the emergence and stabilization of a chronic infection, our model simulations show that two data-derived constraints, namely negative feedback via IL-10 together with antigen-driven proliferation of precursor cells (34,46,47), are sufficient to capture the experimentally observed chronic Th cell response. Further, our model simulations show that the discovery of intermediate proliferative precursor cells that persist during chronic viral infection (34,46) is well in line with previously described infection kinetics (51).…”

“…While several factors have been identified that contribute to the emergence and stabilization of a chronic infection, our model simulations show that two data-derived constraints, namely negative feedback via IL-10 together with antigen-driven proliferation of precursor cells (34,46,47), are sufficient to capture the experimentally observed chronic Th cell response. Further, our model simulations show that the discovery of intermediate proliferative precursor cells that persist during chronic viral infection (34,46) is well in line with previously described infection kinetics (51). Similar progenitor-like phenotypes have been found for exhausted CD8+ T cells (34), thus indicating a general motif of immunological decision-making.…”

“…To derive a quantitative model of Th cell responses in acute and chronic inflammation, we built on two considerations derived from recent experimental data. First, it has been shown that precursor cells maintain a level of reduced proliferative capacity which can sustain the development of fully differentiated cells, even during chronic inflammatory conditions (34,46). Second, terminally differentiated Th1 cells secrete the cytokine IL-10, constituting a feedback circuit modulating the frequency of Tfh cells (47).…”