Functional T cells are capable of supernumerary cell division and longevity

Andrew G. Soerens, Marco Künzli, Clare F. Quarnstrom, Milcah C. Scott, Lee Swanson, Jj Locquiao, Hazem E. Ghoneim, Dietmar Zehn, Benjamin Youngblood, Vaiva Vezys, David Masopust

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Differentiated somatic mammalian cells putatively exhibit species-specific division limits that impede cancer but may constrain lifespans1–3. To provide immunity, transiently stimulated CD8+ T cells undergo unusually rapid bursts of numerous cell divisions, and then form quiescent long-lived memory cells that remain poised to reproliferate following subsequent immunological challenges. Here we addressed whether T cells are intrinsically constrained by chronological or cell-division limits. We activated mouse T cells in vivo using acute heterologous prime–boost–boost vaccinations4, transferred expanded cells to new mice, and then repeated this process iteratively. Over 10 years (greatly exceeding the mouse lifespan)5 and 51 successive immunizations, T cells remained competent to respond to vaccination. Cells required sufficient rest between stimulation events. Despite demonstrating the potential to expand the starting population at least 1040-fold, cells did not show loss of proliferation control and results were not due to contamination with young cells. Persistent stimulation by chronic infections or cancer can cause T cell proliferative senescence, functional exhaustion and death6. We found that although iterative acute stimulations also induced sustained expression and epigenetic remodelling of common exhaustion markers (including PD1, which is also known as PDCD1, and TOX) in the cells, they could still proliferate, execute antimicrobial functions and form quiescent memory cells. These observations provide a model to better understand memory cell differentiation, exhaustion, cancer and ageing, and show that functionally competent T cells can retain the potential for extraordinary population expansion and longevity well beyond their organismal lifespan.

Original languageEnglish (US)
Pages (from-to)762-766
Number of pages5
JournalNature
Volume614
Issue number7949
DOIs
StatePublished - Feb 23 2023

Bibliographical note

Funding Information:
We thank members of the laboratories of D.M. and V.V. for helpful discussions. We thank the University of Minnesota Flow Cytometry resource for cell sorting (J. Motl, T. Martin and R. Arora). This study was supported by National Institutes of Health grants R01 AI084913, R01 AI146032 (D.M.) and T32HL007741 (A.G.S.), and Swiss National Science Foundation grant P2BSP3_200187 (M.K.).

Funding Information:
We thank members of the laboratories of D.M. and V.V. for helpful discussions. We thank the University of Minnesota Flow Cytometry resource for cell sorting (J. Motl, T. Martin and R. Arora). This study was supported by National Institutes of Health grants R01 AI084913, R01 AI146032 (D.M.) and T32HL007741 (A.G.S.), and Swiss National Science Foundation grant P2BSP3_200187 (M.K.).

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.

PubMed: MeSH publication types

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

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