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‘Stem-like’ precursors are the fount to sustain persistent CD8+ T cell responses

Nature Immunology volume 23, pages 836–847 (2022)Cite this article

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Abstract

Virus-specific CD8+ T cells that differentiate in the context of resolved versus persisting infections exhibit divergent phenotypic and functional characteristics, which suggests that their differentiation trajectories are governed by distinct cellular dynamics, developmental pathways and molecular mechanisms. For acute infection, it is long known that antigen-specific T cell populations contain terminally differentiated effector T cells, known as short-lived effector T cells, and proliferation-competent and differentiation-competent memory precursor T cells. More recently, it was identified that a similar functional segregation occurs in chronic infections. A failure to generate proliferation-competent precursor cells in chronic infections and tumors results in the collapse of the T cell response. Thus, these precursor cells are major therapeutic and prophylactic targets of immune interventions. These observations suggest substantial commonality between T cell responses in acute and chronic infections but there are also critical differences. We are therefore reviewing the common features and peculiarities of precursor cells in acute infections, different types of persistent infection and cancer.

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Fig. 1: Illustration of the dynamics of antigen-specific T cell populations following reoccurring infections versus latent or active chronic infections.
Fig. 2: The life cycle of precursor T cells in acute and chronic infection.
Fig. 3: Gene expression signatures of TCF-1-positive, antigen-specific T cells.

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Acknowledgements

D.Z. is supported by a European Research Council consolidator grant (ToCCaTa) and grants from the German Research Foundation (SFB1054 and SFB1371). A.O. is supported by the Swiss National Science Foundation (grant no. IZHRZ0_180552 and grant no. 310030B_185374). E.L. is a CRI Lloyd J. Old STAR (CRI award 3914) and is supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC IG 20676 and AIRC 5×1000 UniCanVax 22757). R.T. is supported by CRC/TRR 179-Project 01 and CRC 1160-Project A02.

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Authors and Affiliations

  1. Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany

    Dietmar Zehn & Gustavo Pereira de Almeida

  2. University Hospital Freiburg, Department of Medicine II, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Robert Thimme

  3. Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

    Enrico Lugli

  4. Institute of Microbiology, ETH Zürich, Zürich, Switzerland

    Annette Oxenius

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  1. Dietmar Zehn
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Correspondence to Dietmar Zehn, Robert Thimme, Enrico Lugli or Annette Oxenius.

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Competing interests

D.Z. has a consulting agreement and research collaboration agreement with Pieris Pharmaceuticals related to manipulation of Tpex cells. E.L. receives research grants from Bristol Myers Squibb and is inventor on a patent describing methods for the generation and isolation of Tscm cells.

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Nature Immunology thanks Axel Kallies and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: L. A. Dempsey, in collaboration with the Nature Immunology team.

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Zehn, D., Thimme, R., Lugli, E. et al. ‘Stem-like’ precursors are the fount to sustain persistent CD8+ T cell responses. Nat Immunol 23, 836–847 (2022). https://doi.org/10.1038/s41590-022-01219-w

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