c-Myb redefines the hierarchy of stem-like T cells

Akin to adult stem cells, precursor exhausted T cells are hierarchically organized, with long-lived CD62L⁺ stem-like T cells at the apex of the system. The transcription factor c-Myb controls the formation, maintenance and therapeutic function of these cells, with important implications for their clinical utilization.

T cell differentiation branches into functional and exhaustion developmental pathways few days after naive T cell activation⁵. When antigen persists, T cell responses are dominated by dysfunctional cells characterized by decreased effector function and increased expression of co-inhibitory receptors, an adaptation that balances antigen control and tissue integrity and is imprinted epigenetically. Whether an antigen-experienced common progenitor with memory and exhaustion potential is formed within the initial divisions after priming has yet to be clarified (Fig. 1). Seminal studies had described a precursor–progeny relationship for T_PEX cells and terminally exhausted T cells (T_EX cells)^2,3 reminiscent of the T_CM–T_EFF hierarchy. Using single-cell transcriptomic analysis (scRNA-seq), Tsui et al. studied the heterogeneity of the exhausted T cells in mice chronically infected with lymphocytic choriomeningitis virus (LCMV-Docile or LCMV-Cl13) and discovered the existence of two main populations within the Tcf7⁺ T_PEX cell compartment⁴: a small subset expressing the genes Sell and Ccr7 (which encode the lymph node–homing molecules selectin L (CD62L) and CCR7, respectively), and a larger population enriched for T_PEX cell–associated mRNAs such as Icos, Xcl1 and Cxcl10 (ref. ³). Slingshot analysis of scRNA-seq data inferred a developmental trajectory originating from CD62L⁺ T_PEX cells, placing them at a hierarchically superior level compared with their CD62L^— counterparts. To experimentally test this differentiation model, the authors spared no effort, performing bulk and single-cell transfer experiments in infection-matched recipients, as well as retrogenic color-barcoding fate mapping. These studies clearly demonstrated a progressive loss of multipotency and repopulation capacity from CD62L⁺ T_PEX cells to CD62L^— T_PEX cells to T_EX cells, which were not able to differentiate into other subsets and exhibited the lowest engraftment and expansion⁴ (Fig. 1). Moreover, when transferred into mice infected with LCMV-Armstrong, which mediates an acute infection, CD62L⁺ T_PEX cells provided enhanced viral control compared with the other exhausted T cell subsets, indicating superior functional reconstitution capacity. Notably, CD62L⁺ T_PEX cells maintained their reconstitution capacity across serial transfers, whereas CD62L^— T_PEX cells almost completely failed to repopulate tertiary hosts⁴. These findings are reminiscent of the reconstituting behavior of LT and ST hematopoietic stem cells after serial transplantation⁶. Thus, by analogy, we will henceforth refer to CD62L⁺ T_PEX cells and CD62L^— T_PEX cells as LT-T_PEX cells and ST-T_PEX cells, respectively. As for LT hematopoietic stem cells, the superior reconstituting capacity of LT-T_PEX cells might be dependent on the safeguarding of their genome integrity. Indeed, during acute infection, CD62L expression has been shown to mark a small subset of memory precursor cells with enhanced capacity to repair DNA damage and reconstitute T cell memory compartment diversity⁷.

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