Modulation of LIGHT-HVEM Costimulation Prolongs Cardiac Allograft Survival

Abstract

LIGHT (TNFSF14), a tumor necrosis factor superfamily member expressed by activated T cells, binds to herpes virus entry mediator (HVEM) which is constitutively expressed by T cells and costimulates T cell activation in a CD28-independent manner. Given interest in regulating the effector functions of T cells in vivo, we examined the role of LIGHT-HVEM costimulation in a murine cardiac allograft rejection model. Normal hearts lacked LIGHT or HVEM mRNA expression, but allografts showed strong expression of both genes from day 3 after transplant, and in situ hybridization and immunohistology-localized LIGHT and HVEM to infiltrating leukocytes. To test the importance of LIGHT expression on allograft survival, we generated LIGHT−/− mice by homologous recombination. The mean survival of fully major histocompatibility complex–mismatched vascularized cardiac allografts in LIGHT−/− mice (10 days, P < 0.05) or cyclosporine A (CsA)-treated LIGHT+/+ mice (10 days, P < 0.05) was only slightly prolonged compared with LIGHT+/+ mice (7 days). However, mean allograft survival in CsA-treated LIGHT−/− allograft recipients (30 days) was considerably enhanced (P < 0.001) compared with the 10 days of mean survival in either untreated LIGHT−/− mice or CsA-treated LIGHT+/+ controls. Molecular analyzes showed that the beneficial effects of targeting of LIGHT in CsA-treated recipients were accompanied by decreased intragraft expression of interferon (IFN)-γ, plus IFN-γ–induced chemokine, inducible protein-10, and its receptor, CXCR3. Treatment of LIGHT+/+ allograft recipients with HVEM-Ig plus CsA also enhanced mean allograft survival (21 days) versus wild-type controls receiving HVEM-Ig (mean of 7 days) or CsA alone (P < 0.001). Our data suggest that T cell to T cell–mediated LIGHT/HVEM-dependent costimulation is a significant component of the host response leading to cardiac allograft rejection.

B7‐H3 promotes acute and chronic allograft rejection

“…Moreover, T cell induction of B7-H3 enhances TCR-driven CD4 and CD8 cell activationinduced proliferation in vitro and in vivo. These data extend the concept of APC-expressed B7-H3 ligating an as yet unknown receptor on T cells and promoting T cell responses, and move B7-H3 into the same functional category as LIGHT [24], i.e. both B7-H3 and LIGHT are inducible molecules on T cells which can ligate cognate receptors and costimulate T:T cell activation.…”

“…Since the presence or absence of B7-H3 affected T celldependent host responses in several allograft models, we also considered whether B7-H3 might be expressed by host T cells in addition to APC and thereby contribute directly to T cell alloresponses in the same way as certain other T:T costimulatory pathways, such as LIGHT and herpes virus entry mediator (HVEM) [24]. Analysis by flow cytometry indeed showed that both CD4 and CD8 T cells activated by TCR stimulation using CD3 mAb alone up-regulated B7-H3 expression, but peak expression required both CD3 and CD28 costimulation (Fig.…”

Adenovirus-mediated LIGHT gene modification in murine B-cell lymphoma elicits a potent antitumor effect

“…Mice deficient in LIGHT show defects in lymph node architecture and reduced cytotoxicity of CTLs. 25,26 In addition, LIGHT has been demonstrated to induce the expression of various chemokines and adhesion molecules that favor the infiltration of lymphocytes into tumor tissues. 19 Interestingly, a recent study showed that LIGHT is constitutively expressed in some human melanoma cells and tumor-derived microvesicles and that tumors expressing LIGHT were associated with increased lymphocytic infiltration.…”

Regulatory T Cell Expression of Herpesvirus Entry Mediator Suppresses the Function of B and T Lymphocyte Attenuator-Positive Effector T Cells

“…With regard to the first question, LIGHT knockout mice showed enhanced cardiac allograft survival using the same model as used in the current studies, and use of HVEM-Ig in WT recipients also prolonged survival (25). These data were interpreted as showing the importance of the LIGHT/HVEM pathway in T cell costimulation, though in retrospect a role for HVEM-Ig binding to BTLA and promoting negative signals within T cells may also have contributed.…”