Targeting lymphocyte activation through the lymphotoxin and LIGHT pathways.
Cytokines mediate key communication pathways essential for regulation of immune responses. Full activation of antigen-responding lymphocytes requires cooperating signals from the tumor necrosis factor (TNF)-related cytokines and their specific receptors. LIGHT, a lymphotoxin-beta (LTbeta)-related TNF family member, modulates T-cell activation through two receptors, the herpesvirus entry mediator (HVEM) and indirectly through the LT-beta receptor. An unexpected finding revealed a non-canonical binding site on HVEM for the immunoglobulin superfamily member, B and T lymphocyte attenuator (BTLA), and an inhibitory signaling protein suppressing T-cell activation. Thus, HVEM can act as a molecular switch between proinflammatory and inhibitory signaling. The non-canonical HVEM-BTLA pathway also acts to counter LTbetaR signaling that promotes the proliferation of antigen-presenting dendritic cells (DCs) within lymphoid tissue microenvironments. These results indicate LTbeta receptor and HVEM-BTLA pathways form an integrated signaling circuit. Targeting these cytokine pathways with specific antagonists (antibody or decoy receptor) can alter lymphocyte differentiation and activation. Alternately, agonists directed at their cell surface receptors can restore homeostasis and potentially reset immune and inflammatory processes, which may be useful in treating autoimmune and infectious diseases and cancer.
Ware
Carl F
CF
Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. cware@liai.org
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000628:therapy; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D025461:Feedback, Physiological; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D053361:Lymphotoxin alpha1, beta2 Heterotrimer / Q000276:immunology* / Q000494:pharmacology*; D053259:Lymphotoxin beta Receptor / Q000276:immunology; D051379:Mice; D020239:Receptor Cross-Talk; D011971:Receptors, Immunologic; D053240:Receptors, Tumor Necrosis Factor, Member 14; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000276:immunology*
C482586:BTLA protein, human; D053361:Lymphotoxin alpha1, beta2 Heterotrimer; D053259:Lymphotoxin beta Receptor; D011971:Receptors, Immunologic; D053240:Receptors, Tumor Necrosis Factor, Member 14; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14