Modulation of LIGHT-HVEM costimulation prolongs cardiac allograft survival.
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)-gamma, plus IFN-gamma-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.
Ye
Qunrui
Q
Millennium Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
Fraser
Christopher C
CC
Gao
Wei
W
Wang
Liqing
L
Busfield
Samantha J
SJ
Wang
Chichung
C
Qiu
Yubin
Y
Coyle
Anthony J
AJ
Gutierrez-Ramos
Jose-Carlos
JC
Hancock
Wayne W
WW
D000818:Animals; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology*; D014181:Transplantation Immunology; D014184:Transplantation, Homologous; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D008565:Membrane Proteins; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha