Differential impact of CD27 and 4-1BB costimulation on effector and memory CD8 T cell generation following peptide immunization

Jane E Willoughby, Jonathan P Kerr, Anne Rogel, Vadim Y Taraban, Sarah L Buchan, Peter W M Johnson, Aymen Al-Shamkhani

Research output: Contribution to journalArticle

Abstract

The factors that determine differentiation of naive CD8 T cells into memory cells are not well understood. A greater understanding of how memory cells are generated will inform of ways to improve vaccination strategies. In this study, we analyzed the CD8 T cell response elicited by two experimental vaccines comprising a peptide/protein Ag and an agonist that delivers a costimulatory signal via CD27 or 4-1BB. Both agonists increased expansion of Ag-specific CD8 T cells compared with Ag alone. However, their capacity to stimulate differentiation into effector and memory cells differed. CD27 agonists promoted increased expression of perforin and the generation of short-lived memory cells, whereas stimulation with 4-1BB agonists favored generation of stable memory. The memory-promoting effects of 4-1BB were independent of CD4 T cells and were the result of programing within the first 2 d of priming. Consistent with this conclusion, CD27 and 4-1BB-stimulated CD8 T cells expressed disparate amounts of IL-2, IFN-γ, CD25, CD71, and Gp49b as early as 3 d after in vivo activation. In addition, memory CD8 T cells, generated through priming with CD27 agonists, proliferated more extensively than did 4-1BB-generated memory cells, but these cells failed to persist. These data demonstrate a previously unanticipated link between the rates of homeostatic proliferation and memory cell attrition. Our study highlights a role for these receptors in skewing CD8 T cell differentiation into effector and memory cells and provides an approach to optimize vaccines that elicit CD8 T cell responses.

Original languageEnglish
Pages (from-to)244-51
Number of pages8
JournalJournal of Immunology
Volume193
Issue number1
DOIs
Publication statusPublished - 1 Jul 2014
Externally publishedYes

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Immunization
T-Lymphocytes
Peptides
Vaccines
Perforin
Interleukin-2
Cell Differentiation
Vaccination
Cell Proliferation
Proteins

Cite this

Willoughby, Jane E ; Kerr, Jonathan P ; Rogel, Anne ; Taraban, Vadim Y ; Buchan, Sarah L ; Johnson, Peter W M ; Al-Shamkhani, Aymen. / Differential impact of CD27 and 4-1BB costimulation on effector and memory CD8 T cell generation following peptide immunization. In: Journal of Immunology. 2014 ; Vol. 193, No. 1. pp. 244-51.
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Differential impact of CD27 and 4-1BB costimulation on effector and memory CD8 T cell generation following peptide immunization. / Willoughby, Jane E; Kerr, Jonathan P; Rogel, Anne; Taraban, Vadim Y; Buchan, Sarah L; Johnson, Peter W M; Al-Shamkhani, Aymen.

In: Journal of Immunology, Vol. 193, No. 1, 01.07.2014, p. 244-51.

Research output: Contribution to journalArticle

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AU - Willoughby, Jane E

AU - Kerr, Jonathan P

AU - Rogel, Anne

AU - Taraban, Vadim Y

AU - Buchan, Sarah L

AU - Johnson, Peter W M

AU - Al-Shamkhani, Aymen

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AB - The factors that determine differentiation of naive CD8 T cells into memory cells are not well understood. A greater understanding of how memory cells are generated will inform of ways to improve vaccination strategies. In this study, we analyzed the CD8 T cell response elicited by two experimental vaccines comprising a peptide/protein Ag and an agonist that delivers a costimulatory signal via CD27 or 4-1BB. Both agonists increased expansion of Ag-specific CD8 T cells compared with Ag alone. However, their capacity to stimulate differentiation into effector and memory cells differed. CD27 agonists promoted increased expression of perforin and the generation of short-lived memory cells, whereas stimulation with 4-1BB agonists favored generation of stable memory. The memory-promoting effects of 4-1BB were independent of CD4 T cells and were the result of programing within the first 2 d of priming. Consistent with this conclusion, CD27 and 4-1BB-stimulated CD8 T cells expressed disparate amounts of IL-2, IFN-γ, CD25, CD71, and Gp49b as early as 3 d after in vivo activation. In addition, memory CD8 T cells, generated through priming with CD27 agonists, proliferated more extensively than did 4-1BB-generated memory cells, but these cells failed to persist. These data demonstrate a previously unanticipated link between the rates of homeostatic proliferation and memory cell attrition. Our study highlights a role for these receptors in skewing CD8 T cell differentiation into effector and memory cells and provides an approach to optimize vaccines that elicit CD8 T cell responses.

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