Immunobiology of lymphotoxin: role in a mouse model of multiple sclerosis

Abstract

Complex immunobiology of lymphotoxin (LT) is due to multiple modalities of signal transduction, involving a soluble homotrimer and membrane-bound heterotrimers that engage at least three different receptors. While LT is crucial for the formation and maintenance of secondary lymphoid organs, its overproduction is observed in autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. Initially, LT was considered pathogenic in the development of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, as demonstrated by the resistance of mice with genetic LT inactivation to EAE induction. However, conflicting observations arose when EAE was induced in RAG1-deficient mice that underwent adoptive bone marrow transfer from LT-deficient mice, thereby calling into question previous conclusions about the role of LT in EAE development. This study aimed to investigate the role of LT in MOG35-55-induced EAE using mice deficient in LT or its membrane receptor, LTR. LT knockout mice used here were designed to avoid the artifact involving TNF gene downregulation in myeloid cells, which occurred in the conventional LT knockout mice. Surprisingly, LT-deficient mice with normal TNF expression developed EAE clinically comparable to wild-type mice. Conversely, genetic inactivation of LTR delayed EAE onset. However, during the later stages of the disease, LTR deletion exacerbated clinical symptoms of EAE. These findings demonstrate that the involvement of LT in EAE development is more complex than previously estimated, and that LTR exhibits diverse functions depending on the disease stage: pathogenic at the early stage and protective at the later stages of EAE.