Cargando…
Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8(+) T-cell proliferation and survival
The CD8(+) T-cell response comprises terminally differentiated effector cells and antigen-experienced memory T cells. The latter encompass central (T(CM)) and effector (T(EM)) memory cells. T(CM) cells are superior in their protection against viral and bacterial challenges and mediation of antitumor...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485779/ https://www.ncbi.nlm.nih.gov/pubmed/26155399 http://dx.doi.org/10.1080/2162402X.2015.1005448 |
_version_ | 1782378815735988224 |
---|---|
author | Abu Eid, Rasha Friedman, Kevin M Mkrtichyan, Mikayel Walens, Andrea King, William Janik, John Khleif, Samir N |
author_facet | Abu Eid, Rasha Friedman, Kevin M Mkrtichyan, Mikayel Walens, Andrea King, William Janik, John Khleif, Samir N |
author_sort | Abu Eid, Rasha |
collection | PubMed |
description | The CD8(+) T-cell response comprises terminally differentiated effector cells and antigen-experienced memory T cells. The latter encompass central (T(CM)) and effector (T(EM)) memory cells. T(CM) cells are superior in their protection against viral and bacterial challenges and mediation of antitumor immunity due to their higher proliferative ability upon antigen re-encounter. Defining a mechanism to enhance T(CM) cells and delay terminal differentiation of CD8(+) T cells is crucial for cancer immune therapy, as it can promote a better tumor immune response. The differentiation of CD8(+) memory T cells is thought to be coordinated by the phosphoinositide 3-kinase (PI3K)/Akt pathway. We, therefore, investigated the role of Akt isoforms in the differentiation and proliferation of memory CD8(+) T cells. We found that Akt1 and Akt2, but not Akt3, drive the terminal differentiation of CD8(+) T cells, and their inhibition enhances the therapeutically superior T(CM) phenotype. Furthermore, the inhibition of Akt1 and Akt2, but not Akt 3, delays CD8(+) T-cell exhaustion and preserves naïve and T(CM) CD8(+) T cells, thus enhancing their proliferative ability and survival and prolonging their cytokine and Granzyme B production ability. Here, we define a mechanism in which proliferative potential, function, and survival of CD8(+) T cells are enhanced by maintaining a reservoir of T(CM) and naïve cells using only Akt1 and Akt2 inhibition. Therefore, our findings strongly suggest the utility of using Akt1 and Akt2 inhibitors to modulate CD8(+) T cells, both for adoptive cell transfer and vaccine-based cancer immune therapies. |
format | Online Article Text |
id | pubmed-4485779 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-44857792016-02-03 Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8(+) T-cell proliferation and survival Abu Eid, Rasha Friedman, Kevin M Mkrtichyan, Mikayel Walens, Andrea King, William Janik, John Khleif, Samir N Oncoimmunology Original Research The CD8(+) T-cell response comprises terminally differentiated effector cells and antigen-experienced memory T cells. The latter encompass central (T(CM)) and effector (T(EM)) memory cells. T(CM) cells are superior in their protection against viral and bacterial challenges and mediation of antitumor immunity due to their higher proliferative ability upon antigen re-encounter. Defining a mechanism to enhance T(CM) cells and delay terminal differentiation of CD8(+) T cells is crucial for cancer immune therapy, as it can promote a better tumor immune response. The differentiation of CD8(+) memory T cells is thought to be coordinated by the phosphoinositide 3-kinase (PI3K)/Akt pathway. We, therefore, investigated the role of Akt isoforms in the differentiation and proliferation of memory CD8(+) T cells. We found that Akt1 and Akt2, but not Akt3, drive the terminal differentiation of CD8(+) T cells, and their inhibition enhances the therapeutically superior T(CM) phenotype. Furthermore, the inhibition of Akt1 and Akt2, but not Akt 3, delays CD8(+) T-cell exhaustion and preserves naïve and T(CM) CD8(+) T cells, thus enhancing their proliferative ability and survival and prolonging their cytokine and Granzyme B production ability. Here, we define a mechanism in which proliferative potential, function, and survival of CD8(+) T cells are enhanced by maintaining a reservoir of T(CM) and naïve cells using only Akt1 and Akt2 inhibition. Therefore, our findings strongly suggest the utility of using Akt1 and Akt2 inhibitors to modulate CD8(+) T cells, both for adoptive cell transfer and vaccine-based cancer immune therapies. Taylor & Francis 2015-02-03 /pmc/articles/PMC4485779/ /pubmed/26155399 http://dx.doi.org/10.1080/2162402X.2015.1005448 Text en © 2015 The Author(s). Published with license by Taylor & Francis Group, LLC http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted. |
spellingShingle | Original Research Abu Eid, Rasha Friedman, Kevin M Mkrtichyan, Mikayel Walens, Andrea King, William Janik, John Khleif, Samir N Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8(+) T-cell proliferation and survival |
title | Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8(+) T-cell proliferation and survival |
title_full | Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8(+) T-cell proliferation and survival |
title_fullStr | Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8(+) T-cell proliferation and survival |
title_full_unstemmed | Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8(+) T-cell proliferation and survival |
title_short | Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8(+) T-cell proliferation and survival |
title_sort | akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory cd8(+) t-cell proliferation and survival |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485779/ https://www.ncbi.nlm.nih.gov/pubmed/26155399 http://dx.doi.org/10.1080/2162402X.2015.1005448 |
work_keys_str_mv | AT abueidrasha akt1and2inhibitiondiminishesterminaldifferentiationandenhancescentralmemorycd8tcellproliferationandsurvival AT friedmankevinm akt1and2inhibitiondiminishesterminaldifferentiationandenhancescentralmemorycd8tcellproliferationandsurvival AT mkrtichyanmikayel akt1and2inhibitiondiminishesterminaldifferentiationandenhancescentralmemorycd8tcellproliferationandsurvival AT walensandrea akt1and2inhibitiondiminishesterminaldifferentiationandenhancescentralmemorycd8tcellproliferationandsurvival AT kingwilliam akt1and2inhibitiondiminishesterminaldifferentiationandenhancescentralmemorycd8tcellproliferationandsurvival AT janikjohn akt1and2inhibitiondiminishesterminaldifferentiationandenhancescentralmemorycd8tcellproliferationandsurvival AT khleifsamirn akt1and2inhibitiondiminishesterminaldifferentiationandenhancescentralmemorycd8tcellproliferationandsurvival |