Lymphotoxin beta receptor (LTbetaR)-/- mice were created by gene targeting. LTbetaR-/- mice lacked Peyer's patches, colon-associated lymphoid tissues, and all lymph nodes. Mucosa patrolling alphaEbeta7high integrin+ T cells were virtually absent. Spleens lost marginal zones; T/B cell segregation and follicular dendritic cell networks were absent. Peanut agglutinin+ cells were aberrantly detectable around central arterioles. In contrast to TNF receptor p55-/- mice, antibody affinity maturation was impaired. Since LTbetaR-/- mice exhibit distinct defects when compared to LTalpha-/- and LTbeta-/- mice, it is suggested that the LTbetaR integrates signals from other TNF family members. Thus, the LTbetaR proves pivotal for the ontogeny of the secondary lymphoid tissues. Furthermore, affinity maturation is dependent on LTalpha1beta2 rather than on LTalpha3.

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.

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.