OX40-mediated memory T cell generation is TNF receptor-associated factor 2 dependent.
Tumor necrosis factor receptor-associated factor 2 (TRAF2), an adapter protein that associates with the cytoplasmic tail of OX40, may play a critical role in OX40-mediated signal transduction. To investigate the in vivo role of TRAF2 in OX40-mediated generation of Ag-specific memory T cells, we bred OVA-specific TCR transgenic mice to TRAF2 dominant-negative (TRAF2 DN) mice. Following Ag stimulation and OX40 engagement of TRAF2 DN T cells in vivo, the number of long-lived OVA-specific T cells and effector T cell function was dramatically reduced when compared with wild-type T cells. We also demonstrate that CTLA-4 is down-regulated following OX40 engagement in vivo and the OX40-specific TRAF2 DN defect was partially overcome by CTLA-4 blockade in vivo. The data provide evidence that TRAF2 is linked to OX40-mediated memory T cell expansion and survival, and point to the down-regulation of CTLA-4 as a possible control element to enhance early T cell expansion through OX40 signaling.
Prell
Rodney A
RA
Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, Portland, OR 97213, USA.
Evans
Dean E
DE
Thalhofer
Colin
C
Shi
Tom
T
Funatake
Castle
C
Weinberg
Andrew D
AD
D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000502:physiology; D060908:CTLA-4 Antigen; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000502:physiology; D007106:Immune Sera / Q000008:administration & dosage; D007156:Immunologic Memory; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D012313:RNA / Q000302:isolation & purification; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D047992:TNF Receptor-Associated Factor 2
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018984:Epitopes, T-Lymphocyte; D006131:Growth Inhibitors; D007106:Immune Sera; D011506:Proteins; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; C505717:Tnfrsf4 protein, mouse; D012313:RNA; D010047:Ovalbumin