Functional T cells are capable of supernumerary cell division and longevity

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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
1. Center for Immunology, Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN, USA.; 2. Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH, USA.; 3. Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.; 4. Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.; 5. Center for Immunology, Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN, USA.

Nature 2023
10.1038/s41586-022-05626-9
English
Soerens AG, Künzli M, Quarnstrom CF, Scott MC, Swanson L, Locquiao JJ, Ghoneim HE, Zehn D, Youngblood B, Vezys V, Masopust D. Functional T cells are capable of supernumerary cell division and longevity. Nature. 2023 Jan 18. doi: 10.1038/s41586-022-05626-9. Epub ahead of print. PMID: 36653453.. Share Research.
Abstract
Differentiated somatic mammalian cells putatively exhibit species-specific division limits that impede cancer but may constrain lifespans1,2,3. 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.
T cells

Differentiated somatic mammalian cells putatively exhibit species-specific division limits that impede cancer but may constrain lifespans1,2,3. 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.

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