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Enhanced CD4 T Cell Responsiveness in the Absence of 4-1BB¹

Seung-Woo Lee^*, Anthony T. Vella, Byoung S. Kwon and Michael Croft^2,*

^* La Jolla Institute for Allergy and Immunology, Division of Molecular Immunology, San Diego, CA 92121; Division of Immunology, University of Connecticut Health Center, Framington, CT 06032; and Immunomodulation Research Center, University of Ulsan, Ulsan, Korea

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.

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