The role of herpesvirus entry mediator as a negative regulator of T cell–mediated responses
Yang Wang, … , Klaus Pfeffer, Yang-Xin Fu
Yang Wang, … , Klaus Pfeffer, Yang-Xin Fu
Published March 1, 2005
Citation Information: J Clin Invest. 2005;115(3):711-717. https://doi.org/10.1172/JCI22982.
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Article Autoimmunity

The role of herpesvirus entry mediator as a negative regulator of T cell–mediated responses

Abstract

Herpesvirus entry mediator (HVEM), a TNF receptor superfamily member, has been previously described as a T cell costimulatory receptor. Surprisingly, HVEM–/– T cells showed enhanced responses to in vitro concanavalin A (ConA) stimulation when compared with WT T cells. Consistent with these findings, HVEM–/– mice exhibited increased morbidity and mortality as compared with WT mice in a model of ConA-mediated T cell–dependent autoimmune hepatitis. HVEM–/– mice produced higher levels of multiple cytokines, which were dependent on the presence of CD4+ T cells. Furthermore, HVEM–/– mice were more susceptible to MOG peptide–induced experimental autoimmune encephalopathy, and they showed increased T cell proliferation and cytokine production in response to antigen-specific challenge. Taken together, our data revealed an unexpected regulatory role of HVEM in T cell–mediated immune responses and autoimmune diseases.

Authors

Yang Wang, Sumit K. Subudhi, Robert A. Anders, James Lo, Yonglian Sun, Sarah Blink, Yugang Wang, Jing Wang, Xiaojuan Liu, Karin Mink, Daniel Degrandi, Klaus Pfeffer, Yang-Xin Fu

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Figure 1

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Targeted disruption of the HVEM locus. (A) Schematic map of the HVEM WT ...
Targeted disruption of the HVEM locus. (A) Schematic map of the HVEM WT locus, the targeting vector, and the inactivated HVEM allele. Black boxes indicate the exons of the HVEM gene. The expected fragment size after hybridization with the 5′ flanking probe (EcoRI digest of genomic DNA) is approximately 17 kb for the WT allele and 10 kb for the inactivated allele. EN-2, engrailed-2 splice acceptor site; lacZ, β-gal expression cassette; pA, polyadenylation signal; DSE, downstream element; neo, neomycin resistance gene cassette; HSV-TK, herpesvirus 1 thymidine kinase expression cassette. (B) Southern blot analysis of mice after germ-line transmission of the HVEM mutation. Hybridization of EcoRI-digested tail DNA of representative mice is shown (E14, control DNA from E14.1 ES cells). (C) Northern blot analysis of HVEM mRNA. Hybridization of spleen RNA is depicted using a murine HVEM cDNA encompassing the complete coding sequence for the extracellular domain. (D) Blood was collected from C57BL/6 (WT) and HVEM –/ – mice, and white blood cells were stained with biotin-labeled rat anti-HVEM mAb and streptavidin-CyChrome. (E) Lymph node cells from WT and HVEM –/ – mice were stained with PE–anti-CD3, biotin-labeled rat anti-HVEM antibody, and streptavidin-CyChrome.