title: Biophysical changes reduce energetic demand in growth factor-deprived lymphocytes.
abstract: Cytokine regulation of lymphocyte growth and proliferation is essential for matching nutrient consumption with cell state. Here, we examine how cellular biophysical changes that occur immediately after growth factor depletion promote adaptation to reduced nutrient uptake. After growth factor withdrawal, nutrient uptake decreases, leading to apoptosis. Bcl-xL expression prevents cell death, with autophagy facilitating long-term cell survival. However, autophagy induction is slow relative to the reduction of nutrient uptake, suggesting that cells must engage additional adaptive mechanisms to respond initially to growth factor depletion. We describe an acute biophysical response to growth factor withdrawal, characterized by a simultaneous decrease in cell volume and increase in cell density, which occurs before autophagy initiation and is observed in both FL5.12 Bcl-xL cells depleted of IL-3 and primary CD8(+) T cells depleted of IL-2 that are differentiating toward memory cells. The response reduces cell surface area to minimize energy expenditure while conserving biomass, suggesting that the biophysical properties of cells can be regulated to promote survival under conditions of nutrient stress.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Vivian C
authors.initials: VC
authors.lastname: Hecht
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Lucas B
authors.initials: LB
authors.lastname: Sullivan
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kimmerling
authors.affiliation: Johns Hopkins Physical Sciences in Oncology Center, Johns Hopkins University, Baltimore, MD 21218 Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218 Department of Pathology and Oncology and Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD 21205.
authors.forename: Dong-Hwee
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Hosios
authors.affiliation: Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Max A
authors.initials: MA
authors.lastname: Stockslager
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Stevens
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139 Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Joon Ho
authors.initials: JH
authors.lastname: Kang
authors.affiliation: Johns Hopkins Physical Sciences in Oncology Center, Johns Hopkins University, Baltimore, MD 21218 Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218 Department of Pathology and Oncology and Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD 21205.
authors.forename: Denis
authors.initials: D
authors.lastname: Wirtz
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139 Dana-Farber Cancer Institute, Boston, MA 02115 mvh@mit.edu srm@mit.edu.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139 Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 mvh@mit.edu srm@mit.edu.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Manalis
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D004734:Energy Metabolism / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000494:pharmacology; D007376:Interleukin-2 / Q000172:deficiency; D007377:Interleukin-3 / Q000172:deficiency; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C502661:Atg7 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D007376:Interleukin-2; D007377:Interleukin-3; D008869:Microtubule-Associated Proteins; D051020:bcl-X Protein; D000071193:Autophagy-Related Protein 7