Danger and OX40 receptor signaling synergize to enhance memory T cell survival by inhibiting peripheral deletion.
This report defines a cell surface receptor (OX40) expressed on effector CD4 T cells, which when engaged in conjunction with a danger signal, rescues Ag-stimulated effector cells from activation-induced cell death in vivo. Specifically, three signals were necessary to promote optimal generation of long-lived CD4 T cell memory in vivo: Ag, a danger signal (LPS), and OX40 engagement. Mice treated with Ag or superantigen (SAg) alone produced very few SAg-specific T cells. OX40 ligation or LPS stimulation, enhanced SAg-driven clonal expansion and the survival of responding T cells. However, when SAg was administered with a danger signal at the time of OX40 ligation, a synergistic effect was observed which led to a 60-fold increase in the number of long-lived, Ag-specific CD4 memory T cells. These data lay the foundation for the provision of increased numbers of memory T cells which should enhance the efficacy of vaccine strategies for infectious diseases, or cancer, while also providing a potential target (OX40) to limit the number of auto-Ag-specific memory T cells in autoimmune disease.
Maxwell
J R
JR
Department of Microbiology, Oregon State University, Corvallis 97331, USA.
Weinberg
A
A
Prell
R A
RA
Vella
A T
AT
D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D017637:Clonal Deletion / Q000276:immunology*; D004768:Enterotoxins / Q000494:pharmacology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D007156:Immunologic Memory / Q000235:genetics; D008024:Ligands; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053278:OX40 Ligand; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D017634:Self Tolerance / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D018089:Superantigens / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D048069:Tumor Necrosis Factors
D000276:Adjuvants, Immunologic; D004768:Enterotoxins; D018984:Epitopes, T-Lymphocyte; D008024:Ligands; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D018089:Superantigens; C505717:Tnfrsf4 protein, mouse; C504586:Tnfsf4 protein, mouse; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D048069:Tumor Necrosis Factors; C026066:enterotoxin A, Staphylococcal