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4-1BB ligand signaling to T cells limits T cell activation.
J Immunol. 2015 Jan 01; 194(1):134-41.JI

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+Show Affiliations

Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and.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.Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and.Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and mick@liai.org.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

25404362

Citation

Eun, So-Young, et al. "4-1BB Ligand Signaling to T Cells Limits T Cell Activation." Journal of Immunology (Baltimore, Md. : 1950), vol. 194, no. 1, 2015, pp. 134-41.
Eun SY, Lee SW, Xu Y, et al. 4-1BB ligand signaling to T cells limits T cell activation. J Immunol. 2015;194(1):134-41.
Eun, S. Y., Lee, S. W., Xu, Y., & Croft, M. (2015). 4-1BB ligand signaling to T cells limits T cell activation. Journal of Immunology (Baltimore, Md. : 1950), 194(1), 134-41. https://doi.org/10.4049/jimmunol.1401383
Eun SY, et al. 4-1BB Ligand Signaling to T Cells Limits T Cell Activation. J Immunol. 2015 Jan 1;194(1):134-41. PubMed PMID: 25404362.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 4-1BB ligand signaling to T cells limits T cell activation. AU - Eun,So-Young, AU - Lee,Seung-Woo, AU - Xu,Yanfei, AU - Croft,Michael, Y1 - 2014/11/17/ PY - 2014/11/19/entrez PY - 2014/11/19/pubmed PY - 2016/2/27/medline SP - 134 EP - 41 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J Immunol VL - 194 IS - 1 N2 - 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. SN - 1550-6606 UR - https://www.unboundmedicine.com/medline/citation/25404362/4_1BB_ligand_signaling_to_T_cells_limits_T_cell_activation_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=25404362 DB - PRIME DP - Unbound Medicine ER -