Journal Article

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

Leonard, Henry J., Rogel, Anne, Buchan, Sarah L., Willoughby, Jane E., Thirdborough, Stephen M., Al-Shamkhani, Aymen

2017

Overview

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 pdk1K465E/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)loCD43lo 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 differentiation were 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.

• Publisher: National Academy of Sciences
• Subject: Animals / Binding Sites - genetics / Biological Sciences / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / Cell differentiation / Cell Line, Tumor / CX3C Chemokine Receptor 1 - immunology / CX3C Chemokine Receptor 1 - metabolism / Immune system / Immunologic Memory - immunology / Immunologic Surveillance - genetics / Immunologic Surveillance - immunology / Immunology and Inflammation / Lymphocytes / Memory / Mice, Inbred C57BL / Mice, Transgenic / Mutation / Neoplasms, Experimental - genetics / Neoplasms, Experimental - immunology / PNAS Plus / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - immunology / Protein Serine-Threonine Kinases - metabolism / Proto-Oncogene Proteins c-akt - immunology / Proto-Oncogene Proteins c-akt - metabolism / Pyruvate Dehydrogenase Acetyl-Transferring Kinase / Receptors, Antigen, T-Cell - immunology / Receptors, Antigen, T-Cell - metabolism / Receptors, CXCR3 - immunology / Receptors, CXCR3 - metabolism / Signal transduction / Signal Transduction - immunology / Tumors / Vaccines