Enhanced CD4 T cell responsiveness in the absence of 4-1BB.
The 4-1BB (CD137) is a member of the TNFR superfamily, and is expressed on several cell types, including activated T cells. Although 4-1BB ligation by agonistic Ab or 4-1BB ligand-expressing APCs can costimulate T cells, the physiological significance of 4-1BB expression in vivo during T cell responses is still being elucidated. In this study, we have addressed the impact on CD4 T cell priming when 4-1BB is absent after gene targeting. Surprisingly, 4-1BB(-/-) mice generated more enhanced effector CD4 T cell responses to OVA protein in adjuvant, even though Ab responses in 4-1BB(-/-) mice were normal. Using an adoptive transfer system with OT-II TCR transgenic CD4 T cells, we found that 4-1BB(-/-) CD4 cells responding in a 4-1BB-sufficient environment had enhanced cell division compared with wild-type cells and displayed augmented clonal expansion during the primary response. This was not due to a developmental defect as 4-1BB-deficient CD4 cells could respond normally to Ag in vitro. These results demonstrate that the absence of 4-1BB can make CD4 T cells hyperresponsive to protein Ag in vivo, suggesting a new unappreciated negative regulatory role of 4-1BB when expressed on a T cell.
Lee
Seung-Woo
SW
La Jolla Institute for Allergy and Immunology, Division of Molecular Immunology, San Diego, CA 92121, USA.
Vella
Anthony T
AT
Kwon
Byoung S
BS
Croft
Michael
M
D000276:Adjuvants, Immunologic / Q000502:physiology; D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D002999:Clone Cells; D005260:Female; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D017475:Receptors, Nerve Growth Factor / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D010047:Ovalbumin