A recombinant vector expressing transgenes for four T-cell costimulatory molecules (OX40L, B7-1, ICAM-1, LFA-3) induces sustained CD4+ and CD8+ T-cell activation, protection from apoptosis, and enhanced cytokine production.
The role of OX40L on the activation of T cells was investigated using poxvirus vectors expressing OX40L alone or in combination with three other T-cell costimulatory molecules: B7-1, ICAM-1, and LFA-3. Poxvirus vector-infected cells were used to stimulate nai;ve or activated CD4(+) and CD8(+) T cells. These studies demonstrate that (a) OX40L plays a role in sustaining the long-term proliferation of CD8(+) T cells in addition to the known effect on CD4(+) T cells following activation, (b) OX40L enhances the production of Th1 cytokines (IL-2, IFN-gamma, and TNF-alpha) from both CD4(+) and CD8(+) while no change in IL-4 expression was observed, and (c) the anti-apoptotic effect of OX40L on T cells is likely the result of sustained expression of anti-apoptotic genes while genes involved in apoptosis are inhibited. In addition, these are the first studies to demonstrate that the combined use of a vector driving the expression of OX40L with three other costimulatory molecules (B7-1, ICAM-1, and LFA-3) both enhances initial activation and then further potentiates sustained activation of nai;ve and effector T cells.
Grosenbach
Douglas W
DW
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, Bethesda, MD 20892-1750, USA.
Schlom
Jeffrey
J
Gritz
Linda
L
Gómez Yafal
Alicia
A
Hodge
James W
JW
D000954:Antigens, Surface; D017209:Apoptosis; D018122:B7-1 Antigen / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018968:CD58 Antigens / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis*; D005822:Genetic Vectors; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D008213:Lymphocyte Activation; D008565:Membrane Proteins; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D011995:Recombination, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D000954:Antigens, Surface; D018122:B7-1 Antigen; D018968:CD58 Antigens; D016207:Cytokines; D008565:Membrane Proteins; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505716:TNFRSF4 protein, human; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1