FOXO3 Regulates CD8 T Cell Memory by T Cell-Intrinsic Mechanisms

PLoS Pathogens

Eui Ho Kim¹  M. Suresh¹  Erin H. Plisch¹  Jeremy A. Sullivan¹  Stanford L. Peng² 

[1] Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America;Virginia Mason Medical Center and Benaroya Research Institute, Seattle, Washington, United States of America

关键词: T cells;    Cytotoxic T cells;    Memory T cells;    Spleen;    Cell staining;    Apoptosis;    Flow cytometry;    Lymph nodes;   

DOI  :  10.1371/journal.ppat.1002533

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

CD8 T cell responses have three phases: expansion, contraction, and memory. Dynamic alterations in proliferation and apoptotic rates control CD8 T cell numbers at each phase, which in turn dictate the magnitude of CD8 T cell memory. Identification of signaling pathways that control CD8 T cell memory is incomplete. The PI3K/Akt signaling pathway controls cell growth in many cell types by modulating the activity of FOXO transcription factors. But the role of FOXOs in regulating CD8 T cell memory remains unknown. We show that phosphorylation of Akt, FOXO and mTOR in CD8 T cells occurs in a dynamic fashion in vivo during an acute viral infection. To elucidate the potentially dynamic role for FOXO3 in regulating homeostasis of activated CD8 T cells in lymphoid and non-lymphoid organs, we infected global and T cell-specific FOXO3-deficient mice with Lymphocytic Choriomeningitis Virus (LCMV). We found that FOXO3 deficiency induced a marked increase in the expansion of effector CD8 T cells, preferentially in the spleen, by T cell-intrinsic mechanisms. Mechanistically, the enhanced accumulation of proliferating CD8 T cells in FOXO3-deficient mice was not attributed to an augmented rate of cell division, but instead was linked to a reduction in cellular apoptosis. These data suggested that FOXO3 might inhibit accumulation of growth factor-deprived proliferating CD8 T cells by reducing their viability. By virtue of greater accumulation of memory precursor effector cells during expansion, the numbers of memory CD8 T cells were strikingly increased in the spleens of both global and T cell-specific FOXO3-deficient mice. The augmented CD8 T cell memory was durable, and FOXO3 deficiency did not perturb any of the qualitative attributes of memory T cells. In summary, we have identified FOXO3 as a critical regulator of CD8 T cell memory, and therapeutic modulation of FOXO3 might enhance vaccine-induced protective immunity against intracellular pathogens.

【 授权许可】

CC BY