The role of herpesvirus entry mediator as a negative regulator of T cell–mediated responses
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
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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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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Increased susceptibility to developing EAE in HVEM –/ – mice. Developmen...
Increased susceptibility to developing EAE in HVEM –/ – mice. Development of EAE was induced in WT mice and HVEM –/ – mice as described in Methods. (A) Mice were observed daily and scored. The mean clinical score plotted against time is shown. Five mice per group were tested. (B–D) Stronger MOG-specific T cell responses are detected in HVEM –/ – mice. The mice were immunized s.c. with 100 μg of MOG 35–55 emulsified in CFA (without toxin). Ten days later, DLN cells from the mice were isolated and cultured with various concentrations of MOG 35–55 peptide in complete RPMI-1640 medium for 5 days for proliferation analysis (B). Stronger responses were detected in the cells from the HVEM –/ – group at concentrations of 1, 5, and 25 μg (P < 0.05). The number of IFN-producing cells was determined by ELISPOT (C). Cells producing higher levels of IFN were detected in HVEM –/ – mice (P < 0.001). DLN cells were stimulated with antigens overnight for ELISPOT to determine the frequency of antigen-specific T cells (D). DLN cells from HVEM –/ – mice contained a higher frequency of IFN-producing cells (P < 0.001). One of 3 experiments is presented.