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

Abstract

Soon after activation, CD4⁺ T cells are segregated into BCL6⁺ follicular helper (Tfh) and BCL6^- effector (Teff) T cells. Here, we explored how these subsets are maintained during chronic antigen stimulation using the mouse chronic LCMV infection model. Using single cell-transcriptomic and epigenomic analyses, we identified a population of PD-1⁺ TCF-1⁺ CD4⁺ T cells with memory-like features. TCR clonal tracing and adoptive transfer experiments demonstrated that these cells have self-renewal capacity and continue to give rise to both Teff and Tfh cells, thus functioning as progenitor cells. Conditional deletion experiments showed Bcl6-dependent development of these progenitors, which were essential for sustaining antigen-specific CD4⁺ T cell responses to chronic infection. An analogous CD4⁺ T cell population developed in draining lymph nodes in response to tumors. Our study reveals the heterogeneity and plasticity of CD4⁺ T cells during persistent antigen exposure and highlights their population dynamics through a stable, bipotent intermediate state.

Keywords: CD4(+) T cells; anti-tumor immunity; chronic viral infection; effector T cells; follicular helper T cells; progenitor cells; single-cell genomics.