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

Authors: Rogel, A., Willoughby, J.E., Buchan, S.L., Leonard, H.J., Thirdborough, S.M. and Al-Shamkhani, A.

Journal: Proceedings of the National Academy of Sciences of the United States of America

Volume: 114

Issue: 7

Pages: E1178-E1187

eISSN: 1091-6490

ISSN: 0027-8424

DOI: 10.1073/pnas.1611299114

Abstract:

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.

Source: Scopus

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

Authors: Rogel, A., Willoughby, J.E., Buchan, S.L., Leonard, H.J., Thirdborough, S.M. and Al-Shamkhani, A.

Journal: Proc Natl Acad Sci U S A

Volume: 114

Issue: 7

Pages: E1178-E1187

eISSN: 1091-6490

DOI: 10.1073/pnas.1611299114

Abstract:

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.

Source: PubMed

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

Authors: Rogel, A., Willoughby, J.E., Buchan, S.L., Leonard, H.J., Thirdborough, S.M. and Al-Shamkhani, A.

Journal: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Volume: 114

Issue: 7

Pages: E1178-E1187

ISSN: 0027-8424

DOI: 10.1073/pnas.1611299114

Source: Web of Science (Lite)

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

Authors: Rogel, A., Willoughby, J.E., Buchan, S.L., Leonard, H.J., Thirdborough, S.M. and Al-Shamkhani, A.

Journal: Proc Natl Acad Sci U S A

Volume: 114

Issue: 7

Pages: E1178-E1187

eISSN: 1091-6490

DOI: 10.1073/pnas.1611299114

Abstract:

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)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.

Source: Manual

Preferred by: Sarah Buchan

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

Authors: Rogel, A., Willoughby, J.E., Buchan, S.L., Leonard, H.J., Thirdborough, S.M. and Al-Shamkhani, A.

Journal: Proceedings of the National Academy of Sciences of the United States of America

Volume: 114

Issue: 7

Pages: E1178-E1187

eISSN: 1091-6490

ISSN: 0027-8424

DOI: 10.1073/pnas.1611299114

Abstract:

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)^loCD43^lo 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.

Source: Europe PubMed Central