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

Immunity. 2022 Jul 12;55(7):1200-1215.e6. doi: 10.1016/j.immuni.2022.05.003. Epub 2022 May 27.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigens*
  • Cell Differentiation
  • Mice
  • Proto-Oncogene Proteins c-bcl-6 / genetics
  • Stem Cells
  • T-Lymphocytes, Helper-Inducer*


  • Antigens
  • Bcl6 protein, mouse
  • Proto-Oncogene Proteins c-bcl-6