T-cell costimulation in a new LIGHT

Abstract

Tamada, K. et al. (2000) Modulation of T-cell-mediated immunity in tumour and graft-versus-host disease models through the LIGHT costimulatory pathway. Nat. Med. 6, 283–289Direct manipulation of T-cell responses is the goal of many therapies for immunological disorders. Stimulation of the B7–CD28 costimulatory pathway is associated with an increased anti-tumour immune response, whereas blocking this pathway inhibits the progression of a potentially fatal complication of bone-marrow transplantation – graft-versus-host disease (GVHD; in which allogeneic lymphocytes react against host tissue in an immunocompromised recipient).Tamada et al. have identified a T-cell costimulatory pathway involving a recently described member of the tumour necrosis factor family, LIGHT. LIGHT [whose name derives from: homologous to lymphotoxins, shows inducible expression, and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator (HVEM), a receptor expressed by T lymphocytes] binds with high affinity to the T-cell receptor HVEM and to the lymphotoxin β receptor (LTβR) found on monocytes and stromal cells. Blocking HVEM is known to inhibit allogeneic mixed lymphocyte reactions.The group show that LIGHT stimulates mouse T-cell proliferation in the presence, but not the absence, of immobilized anti-CD3 antibody – demonstrating the requirement of an antigenic signal. Furthermore, LIGHT costimulates CD28− T cells to the same degree as CD28+ T cells, indicating a CD28-independent pathway.The isolation of a mouse LIGHT homologue enabled investigation of these costimulatory effects in vivo. Tumour regression was observed in mice injected with LIGHT cDNA, an effect reversed by depletion of CD8+ T cells, indicating the costimulation of cytotoxic T lymphocyte (CTL) anti-tumour responses.Conversely, the treatment of GVHD aims to reduce CTL responses. By infusing a soluble form of the LIGHT receptor lymphotoxin β receptor (LTβR-Ig), Tanaka et al. prevented the onset of GVHD in immunocompromised recipient mice – suggesting that blocking the LIGHT costimulatory pathway prevents disease progression.Questions remain over the relevance of other possible functions of LIGHT, and of alternative receptors. Nevertheless, investigation of this previously unknown costimulatory pathway could provide novel therapeutic targets for the treatment of transplantation and cancer.