CD8+ T Lymphocyte Self-Renewal during Effector Cell Determination
Wen-Hsuan W. Lin,
Simone A. Nish,
Bonnie Yen,
Yen-Hua Chen,
William C. Adams,
Radomir Kratchmarov,
Nyanza J. Rothman,
Avinash Bhandoola,
Hai-Hui Xue,
Steven L. Reiner
Affiliations
Wen-Hsuan W. Lin
Department of Microbiology and Immunology and Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
Simone A. Nish
Department of Microbiology and Immunology and Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
Bonnie Yen
Department of Microbiology and Immunology and Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
Yen-Hua Chen
Department of Microbiology and Immunology and Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
William C. Adams
Department of Microbiology and Immunology and Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
Radomir Kratchmarov
Department of Microbiology and Immunology and Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
Nyanza J. Rothman
Department of Microbiology and Immunology and Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
Avinash Bhandoola
T-Cell Biology and Development Unit, Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
Hai-Hui Xue
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Steven L. Reiner
Department of Microbiology and Immunology and Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
Selected CD8+ T cells must divide, produce differentiated effector cells, and self-renew, often repeatedly. We now show that silencing expression of the transcription factor TCF1 marks loss of self-renewal by determined effector cells and that this requires cell division. In acute infections, the first three CD8+ T cell divisions produce daughter cells with unequal proliferative signaling but uniform maintenance of TCF1 expression. The more quiescent initial daughter cells resemble canonical central memory cells. The more proliferative, effector-prone cells from initial divisions can subsequently undergo division-dependent production of a TCF1-negative effector daughter cell along with a self-renewing TCF1-positive daughter cell, the latter also contributing to the memory cell pool upon resolution of infection. Self-renewal in the face of effector cell determination may promote clonal amplification and memory cell formation in acute infections, sustain effector regeneration during persistent subclinical infections, and be rate limiting, but remediable, in chronic active infections and cancer.
