Cooperation between molecular targets of costimulation in promoting T cell persistence and tumor regression.
Costimulation regulates multiple cellular processes of T cells inducing proliferation, expansion, and survival. The molecular targets of costimulation might then be useful to augment T cell activities. Two defined targets of costimulatory signals in primary T cells are the anti-apoptotic bcl-2 family molecule Bcl-x(L), and survivin, an inhibitor of apoptosis family member that might regulate both cell division and survival. However, the relative importance of, and relationship between, these molecules in primary T cells is not clear. To understand whether they have overlapping or cooperative functions, we used retrovirus-mediated transduction to introduce Bcl-x(L) and survivin separately, or together linked by a 2A picornavirus self-cleaving peptide, into Ag-responding CD8(+) T cells. We found that CD8(+) effector T cells expressing both Bcl-x(L) and survivin strongly expanded at an early stage and had a long-term survival advantage over cells transduced with either molecule alone. In vivo, with response to tumor-expressed Ag following adoptive T cell transfer, Ag-reactive CD8(+) T cells expressing both Bcl-x(L) and survivin displayed greatly enhanced tumor protective activity compared with CD8(+) T cells expressing either molecule introduced separately. These results indicate that Bcl-x(L) and survivin can critically contribute in a cooperative, nonredundant manner to augment the accumulation and persistence of CD8(+) T cells following encounter with Ag. The data provide new insights into why costimulatory signals might need to be sustained over time and suggest a potential novel approach to augment cellular immunotherapy for cancer.
Zhao
Baohua
B
Department of Microbiology and Immunology and Pennsylvania State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
Song
Aihua
A
Haque
Rizwanul
R
Lei
Fengyang
F
Weiler
Lauren
L
Xiong
Xiaofang
X
Wu
Yuzhang
Y
Croft
Michael
M
Song
Jianxun
J
D000818:Animals; D000941:Antigens; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003432:Cross-Linking Reagents; D051034:Inhibitor of Apoptosis Proteins; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology*; D009369:Neoplasms / Q000628:therapy*; D012097:Repressor Proteins; D000077022:Survivin; D014161:Transduction, Genetic; D051020:bcl-X Protein / Q000235:genetics / Q000502:physiology*
D000941:Antigens; D051017:Apoptosis Regulatory Proteins; C117749:Birc5 protein, mouse; D003432:Cross-Linking Reagents; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D012097:Repressor Proteins; D000077022:Survivin; D051020:bcl-X Protein