Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes

Most tumor cells function poorly as antigen-presenting cells in part because they do not express costimulatory molecules. To provide costimulation to T lymphocytes that recognize tumor cells, we constructed a CD28-like receptor specific for GD2, a ganglioside overexpressed on the surface of neurobla...

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Bibliographic Details
Published in:The Journal of experimental medicine 1998-08, Vol.188 (4), p.619-626
Main Authors: Krause, A, Guo, H F, Latouche, J B, Tan, C, Cheung, N K, Sadelain, M
Format: Article
Language:English
Subjects:
adoptive cell therapy
Animals
Antibodies, Anti-Idiotypic - immunology
Apoptosis
BASIC BIOLOGICAL SCIENCES
CD28 Antigens - genetics
CD28 Antigens - immunology
CD28 Antigens - metabolism
CD3 Complex - immunology
Cell Division
Cell Survival
Cells, Cultured
chimeric receptors
costimulation
ganglioside
Gangliosides - immunology
Gangliosides - pharmacology
gene transfer
Histocompatibility Antigens Class II - immunology
Humans
immunology
Interleukin-2 - biosynthesis
Interleukin-2 - metabolism
Lymphocyte Activation
Mice
Peptides - immunology
Receptors, Interleukin-2 - biosynthesis
Recombinant Fusion Proteins - genetics
Recombinant Fusion Proteins - immunology
research and experimental medicine
Signal Transduction
T-Lymphocytes - immunology
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Summary:Most tumor cells function poorly as antigen-presenting cells in part because they do not express costimulatory molecules. To provide costimulation to T lymphocytes that recognize tumor cells, we constructed a CD28-like receptor specific for GD2, a ganglioside overexpressed on the surface of neuroblastoma, small-cell lung carcinoma, melanoma, and other human tumors. Recognition of GD2 was provided by a single-chain antibody derived from the GD2-specific monoclonal antibody 3G6. We demonstrate that the chimeric receptor 3G6-CD28 provides CD28 signaling upon specific recognition of the GD2 antigen on tumor cells. Human primary T lymphocytes retrovirally transduced with 3G6-CD28 secrete interleukin 2, survive proapoptotic culture conditions, and selectively undergo clonal expansion in the presence of an antiidiotypic antibody specific for 3G6-CD28. Polyclonal CD8(+) lymphocytes expressing 3G6-CD28 are selectively expanded when cultured with cells expressing allogeneic major histocompatibility complex class I together with GD2. Primary T cells given such an antigen-dependent survival advantage should be very useful to augment immune responses against tumor cells.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.188.4.619