Chapter 34 - Lymphotoxins

Abstract

This chapter focuses on recent aspects of LTαβ and LTα as ligands for LTβR and TNFR, respectively. Additional reviews are available on the general features of the TNF superfamily and LT (lymphotoxin), which was originally identified as a soluble factor produced by lymphocytes that was cytotoxic to tumor cells, and later recognized as a cell surface protein on activated T cells. Two distinct forms of LT are recognized, the original secreted form that is homologous to tumor necrosis factor (TNF), known as LTα, and the membrane form, comprised of a heterocomplex between LTα and a second related protein LTβ. LTα and TNF both bind the cell surface receptors TNFR1 and TNFR2, whereas the LTαβ complex binds a distinct receptor with specificity determined by the LTβ subunit. The receptors for LT and TNF are members of a corresponding family of cell surface and secreted proteins each with distinct roles in physiology. Gene disruption studies in mice have linked LTαβ-LTβR signaling to lymphoid organogenesis, splenic architecture, and differentiation of NK and NK-T cells, whereas LTα-TNFR1 signaling has been linked to the formation of tertiary lymphoid tissues, and inflammation. The shared ligand specificity revealed by the interaction of LTβR with the LT-related ligand LIGHT, which binds to the TNFR superfamily member, HVEM (herpes virus entry mediator), and can engage LTα. This shared receptor usage indicates these ligands form an integrated network of signaling systems that orchestrate immune function, underscored by their conserved genetic organization, and linkage to the major histocompatibility gene complex (MHC).