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 TPEX cells and terminally exhausted T cells (TEX cells)2,3 reminiscent of the TCM–TEFF 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+ TPEX 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 TPEX cell–associated mRNAs such as Icos, Xcl1 and Cxcl10 (ref. 3). Slingshot analysis of scRNA-seq data inferred a developmental trajectory originating from CD62L+ TPEX 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+ TPEX cells to CD62L— TPEX cells to TEX 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+ TPEX cells provided enhanced viral control compared with the other exhausted T cell subsets, indicating superior functional reconstitution capacity. Notably, CD62L+ TPEX cells maintained their reconstitution capacity across serial transfers, whereas CD62L— TPEX 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+ TPEX cells and CD62L— TPEX cells as LT-TPEX cells and ST-TPEX cells, respectively. As for LT hematopoietic stem cells, the superior reconstituting capacity of LT-TPEX 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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L.G. is an inventor on a patent that describes methods for generating and isolating TSCM cells and on a patent that describes the use of c-Myb to enhance T cell therapy efficacy. L.G. has consulting agreements with Lyell Immunopharma, Advaxis Immunotherapies and Instil Bio, is on the scientific advisory boards of Poseida Therapeutics and Kiromic, and is a stockholder of Poseida Therapeutics. C.H. declares no competing interests.
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Heuser, C., Gattinoni, L. c-Myb redefines the hierarchy of stem-like T cells. Nat Immunol 23, 1405–1407 (2022). https://doi.org/10.1038/s41590-022-01319-7
Published: 03 October 2022
Issue Date: October 2022