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Nat Commun. 2015 Feb 24;6:6301. doi: 10.1038/ncomms7301.

Real-time tracking of cell cycle progression during CD8+ effector and memory T-cell differentiation.

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Immune Imaging Program, Centenary Institute for Cancer Medicine and Cell Biology, Newtown, New South Wales 2042, Australia.
1] Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia.
Cell Innovator Co., Ltd., Fukuoka 812-8581, Japan.
Laboratory for Autoimmune Regulation, RIKEN Research Center for Allergy and Immunology, Yokohama 230-0045, Japan.
Laboratory for Cell Function and Dynamics, Brain Science Institute, RIKEN, Saitama 351-0198, Japan.
1] Immune Imaging Program, Centenary Institute for Cancer Medicine and Cell Biology, Newtown, New South Wales 2042, Australia [2] Discipline of Dermatology, Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia [3] Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia.


The precise pathways of memory T-cell differentiation are incompletely understood. Here we exploit transgenic mice expressing fluorescent cell cycle indicators to longitudinally track the division dynamics of individual CD8(+) T cells. During influenza virus infection in vivo, naive T cells enter a CD62L(intermediate) state of fast proliferation, which continues for at least nine generations. At the peak of the anti-viral immune response, a subpopulation of these cells markedly reduces their cycling speed and acquires a CD62L(hi) central memory cell phenotype. Construction of T-cell family division trees in vitro reveals two patterns of proliferation dynamics. While cells initially divide rapidly with moderate stochastic variations of cycling times after each generation, a slow-cycling subpopulation displaying a CD62L(hi) memory phenotype appears after eight divisions. Phenotype and cell cycle duration are inherited by the progeny of slow cyclers. We propose that memory precursors cell-intrinsically modulate their proliferative activity to diversify differentiation pathways.

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