Constitutive reductions in mTOR alter cell size, immune cell development, and antibody production

Shuling Zhang, Julie A. Readinger, Wendy DuBois, Mirkka Janka-Junttila, Richard Robinson, Margaret Pruitt, Val Bliskovsky, Julie Z. Wu, Kaori Sakakibara, Jyoti Patel, Carole A. Parent, Lino Tessarollo, Pamela L. Schwartzberg, Beverly A. Mock

Research output: Contribution to journalArticlepeer-review

91 Scopus citations

Abstract

Mammalian TOR (mTOR) regulates cell growth, proliferation, and migration. Because mTOR knock-outs are embryonic lethal, we generated a viable hypomorphic mouse by neo-insertion that partially disrupts mTOR transcription and creates a potential physiologic model of mTORC1/ TORC2 inhibition. Homozygous knock-in mice exhibited reductions in body, organ, and cell size. Although reductions in most organ sizes were proportional to decreased body weight, spleens were disproportionately smaller. Decreases in the total number of T cells, particularly memory cells, and reduced responses to chemokines suggested alterations in T-cell homing/homeostasis. T-cell receptor-stimulated T cells proliferated less, produced lower cytokine levels, and expressed FoxP3. Decreased neutrophil numbers were also observed in the spleen, despite normal development and migration in the bone marrow. However, B-cell effects were most pronounced, with a partial block in B-cell development in the bone marrow, altered splenic populations, and decreases in proliferation, antibody production, and migration to chemokines. Moreover, increased AKT Ser473 phosphorylation was observed in activated B cells, reminiscent of cancers treated with rapamycin, and was reduced by a DNA-pk inhibitor. Thus, mTOR is required for the maturation and differentiation of multiple immune cell lineages. These mice provide a novel platform for studying the consequences of constitutively reduced mTORC1/TORC2 activity.

Original languageEnglish (US)
Pages (from-to)1228-1238
Number of pages11
JournalBlood
Volume117
Issue number4
DOIs
StatePublished - Jan 27 2011

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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