Akt signaling is critical for memory CD8(+) T-cell development and tumor immune surveillance

作者：Rogel Anne; Willoughby Jane E; Buchan Sarah L; Leonard Henry J; Thirdborough Stephen M; Al Shamkhani Aymen^*

来源：Proceedings of the National Academy of Sciences, 2017, 114(7): E1178-E1187.

DOI：10.1073/pnas.1611299114

• PKB
• cytotoxic T cells
• vaccines
• immunotherapy
• cancer

Memory CD8(+) T cells confer long-term immunity against tumors, and anticancer vaccines therefore should maximize their generation. Multiple memory CD8(+) T-cell subsets with distinct functional and homing characteristics exist, but the signaling pathways that regulate their development are ill defined. Here we examined the role of the serine/threonine kinase Akt in the generation of protective immunity by CD8(+) T cells. Akt is known to be activated by the T-cell antigen receptor and the cytokine IL-2, but its role in T-cell immunity in vivo has not been explored. Using CD8(+) T cells from pdk1(K465E/K465E) knockin mice, we found that decreased Akt activity inhibited the survival of T cells during the effector-to-memory cell transition and abolished their differentiation into C-X-C chemokine receptor 3 (CXCR3)(io)CD43(io) effector-like memory cells. Consequently, antitumor immunity by CD8(+) T cells that display defective Akt signaling was substantially diminished during the memory phase. Reduced memory T-cell survival and altered memory cell differentiationwere associated with up-regulation of the proapoptotic protein Bim and the T-box transcription factor eomesodermin, respectively. These findings suggest an important role for effector-like memory CD8(+) T cells in tumor immune surveillance and identify Akt as a key signaling node in the development of protective memory CD8(+) T-cell responses.

• 出版日期2017-2-14