Constitutive Expression of LIGHT on T Cells Leads to Lymphocyte Activation, Inflammation, and Tissue Destruction

Abstract

LIGHT, a member of the TNF family of cytokines (homologous to lymphotoxin, exhibits inducible expression and competes with HSV glycoprotein D for herpesvirus entry mediator, a receptor expressed on T cells), is induced on activated T cells and mediates costimulatory and antitumor activity in vitro. Relatively little information is available on the in vivo effects of LIGHT expression, particularly within the T cell compartment. In this work, we describe transgenic mice that express human LIGHT under the control of the CD2 promoter, resulting in constitutive transgene expression in cells of the T lymphocyte lineage. LIGHT-transgenic animals exhibit abnormalities in both lymphoid tissue architecture and the distribution of lymphocyte subsets. They also show signs of inflammation that are most severe in the intestine, along with tissue destruction of the reproductive organs. These LIGHT-mediated effects were recapitulated when immune-deficient mice were reconstituted with bone marrow from LIGHT-transgenic donor mice. T cells in the LIGHT-transgenic mice have an activated phenotype and mucosal T cells exhibit enhanced Th1 cytokine activity. The results indicate that LIGHT may function as an important regulator of T cell activation, and implicate LIGHT signaling pathways in inflammation focused on mucosal tissues.

Mouse T cells receive costimulatory signals from LIGHT, a TNF family member

“…In addition, recent studies showed that LIGHT transgenic mice overexpressing LIGHT on T cells have enhanced immune response. 27,28 This result does not fit to the model in which LIGHT transduces negative signals into T cells, because if so, the LIGHT transgenic mice should have suppressed immune response instead. Lastly, there are about 4 to 5 TNF family members capable of transducing signals into cells, but none of them transduces a negative one.…”

CD40L expressed from the canarypox vector, ALVAC, can boost immunogenicity of HIV-1 canarypox vaccine in mice and enhance the in vitro expansion of viral specific CD8+ T cell memory responses from HIV-1-infected and HIV-1-uninfected individuals

“…One advantage of canarypox vector is its high-profiled safety, which has been demonstrated in both animal studies and clinical trials [5,9,29,48]. Another advantage of canarypox vector is that as a DNA virus that can only abortively infect mammalian cells, the target gene will be expressed transiently, which may be especially important for the expression of costimulatory molecules, such as CD40L, since long-term presence of costimulatory molecules might lead to autoimmunity or immunosuppression [49][50][51]. In our current study, we found no discernible signs of adverse effects of CD40L-expressing canarypox vector when used in mice.…”

High levels of soluble herpes virus entry mediator in sera of patients with allergic and autoimmune diseases

“…Since the expression of LIGHT (the HVEM ligand) on T cells is induced after activation, T cell activation through HVEM signaling may involve interaction of T cells with each other. Indeed, blockade of HVEM-LIGHT interactions inhibits proliferation of highly purified T cells in response to TCR stimulation (Shaikh et al, 2001). Thus, co-stimulation via HVEM depends on the presence of LIGHT on T cells (Morel et al, 2000;Scheu et al, 2002).…”