Xia Y, Sandor K, Pai JA, Daniel B, Raju S, Wu R, Hsiung S, Qi Y, Yangdon T, Okamoto M, Chou C, Hiam-Galvez KJ, Schreiber RD, Murphy KM, Satpathy AT, Egawa T.
Immunity, 25 May 2022

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.