title: 4-1BB ligand signaling to T cells limits T cell activation.
abstract: 4-1BB ligand (4-1BBL) and its receptor, 4-1BB, are both induced on T cells after activation, but little is known about the role of 4-1BBL. In this study we show that 4-1BBL can transmit signals that limit T cell effector activity under tolerogenic conditions. Cross-linking 4-1BBL inhibited IL-2 production in vitro, primarily with suboptimal TCR stimulation. Furthermore, naive 4-1BBL-deficient OT-II transgenic T cells displayed a greater conversion to effector T cells in vivo when responding to soluble OVA peptide in wild-type hosts, whereas development of Foxp3(+) regulatory T cells was not altered. A greater number of effector T cells also differentiated from naive wild-type OT-II T cells when transferred into 4-1BB-deficient hosts, suggesting that APC-derived 4-1BB is likely to trigger 4-1BBL. Indeed, effector T cells that could not express 4-1BBL accumulated in larger numbers in vitro when stimulated with 4-1BB-expressing mesenteric lymph node dendritic cells. 4-1BBL was expressed on T cells when Ag presentation was limiting, and 4-1BBL was aberrantly expressed at very high levels on T cells that could not express 4-1BB. Trans-ligation, Ab capture, and endocytosis experiments additionally showed that T cell-intrinsic 4-1BB regulated internalization of membrane 4-1BBL, implying that the strong induction of 4-1BB on T cells may counteract the suppressive function of 4-1BBL by limiting its availability. These data suggest that 4-1BBL expressed on T cells can restrain effector T cell development, creating a more favorable regulatory T cell to effector cell balance under tolerogenic conditions, and this may be particularly active in mucosal barrier tissues where 4-1BB-expressing regulatory dendritic cells present Ag.
authors.affiliation: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and.
authors.forename: So-Young
authors.initials: SY
authors.lastname: Eun
authors.affiliation: Laboratory of Immune Regulation, Division of Integrative Biosciences and Biotechnology, Biotechnology Center, Pohang University of Science and Technology, Pohang-Si, Gyeongsangbuk-Do 790-784, Korea.
authors.forename: Seung-Woo
authors.initials: SW
authors.lastname: Lee
authors.affiliation: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and mick@liai.org.
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
mesh_terms: D053330:4-1BB Ligand / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology*; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology*
chemical_list: D053330:4-1BB Ligand; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D010047:Ovalbumin