Lymphotoxin is a signaling protein, a type of cytokine, used by the immune system to carry messages between cells to organize defenses and coordinate responses to infection and injury. It is a member of the tumor necrosis factor (TNF) superfamily, a group of proteins involved in regulating immune cell functions. Lymphotoxin’s actions contribute to both the development of the immune system’s physical structures and its ongoing operations in adulthood.
The Lymphotoxin Family and Its Receptors
The term lymphotoxin (LT) refers not to one molecule, but to a small family of related proteins, primarily Lymphotoxin-alpha (LT-α) and Lymphotoxin-beta (LT-β). LT-α is versatile and can be secreted by activated immune cells, such as T and B lymphocytes, as a soluble protein. In this form, it assembles into a group of three identical units called a homotrimer (LT-α3), which was previously known as TNF-beta.
LT-α can also partner with LT-β, a protein that stays anchored to a cell’s surface. They combine to form a membrane-bound heterotrimer, most commonly a complex of one LT-α and two LT-β molecules (LT-α1/β2). This membrane-anchored complex acts as a signal presented only through direct cell-to-cell contact, which dictates which cells it can communicate with and what message it sends.
These lymphotoxin complexes function like keys that fit into specific locks, known as receptors, on the surface of other cells. The soluble LT-α3 homotrimer primarily binds to two receptors, TNFR1 and TNFR2, which it shares with TNF. In contrast, the membrane-bound LT-α1/β2 complex binds almost exclusively to its own specific receptor, the Lymphotoxin Beta Receptor (LTβR).
Role in Lymphoid Organ Development
During embryonic development, lymphotoxin signaling provides a blueprint for building parts of the immune system. It is responsible for forming secondary lymphoid organs, the structures where immune responses are organized. These include lymph nodes and specialized tissues in the gut called Peyer’s patches. Without functioning lymphotoxin signals, these immune centers fail to develop.
The process begins when lymphoid tissue inducer (LTi) cells display the membrane-bound LT-α1/β2 complex. These LTi cells interact with local structural cells, called stromal cells, that express the LTβR. This interaction signals the stromal cells to differentiate and produce chemical attractants called chemokines.
These chemokines, in turn, attract more immune cells, including T cells and B cells, to the designated site. This influx of cells leads to the assembly and organization of the new lymphoid organ, complete with distinct zones for different immune cell types.
Function in the Adult Immune Response
In a mature immune system, lymphotoxin transitions from a developmental architect to an active field commander orchestrating responses to infections. When immune cells detect a pathogen, they use lymphotoxin to amplify the local inflammatory response. This signaling induces cells lining blood vessels to express adhesion molecules, which act like velcro to catch passing white blood cells and help them move into infected tissue. The signal also stimulates nearby cells to release more chemokines, which guide immune cells toward the threat.
Beyond recruiting help, lymphotoxin can also order a cell to self-destruct through a process called apoptosis, or programmed cell death. This function is useful for eliminating compromised cells, such as those infected with a virus or those that have become cancerous. By binding to receptors like TNFR1, lymphotoxin can trigger an internal cascade that causes the target cell to die, preventing the spread of infection or the growth of a tumor.
Connection to Disease
When the lymphotoxin system is not properly regulated, its powerful functions can contribute to disease. In several autoimmune disorders, the immune system mistakenly attacks the body’s own tissues, and lymphotoxin signaling can perpetuate this assault. In rheumatoid arthritis, for example, lymphotoxin drives the formation of ectopic lymphoid structures within the joint tissue, which sustain chronic inflammation and lead to the destruction of cartilage and bone.
A similar process occurs in multiple sclerosis, where lymphotoxin signaling is implicated in forming inflammatory lesions in the central nervous system. It helps immune cells cross the protective blood-brain barrier and attack the myelin sheath that insulates nerve fibers. In animal models of the disease, blocking the lymphotoxin pathway has been shown to reduce the size and number of these damaging inflammatory sites.
The role of lymphotoxin in cancer is complex. Its ability to induce apoptosis can help kill tumor cells, and its absence has been linked to increased tumor growth in animal studies. However, the chronic inflammation driven by lymphotoxin can also create a microenvironment that supports tumor survival. In some cancers, like certain lymphomas and liver cancer, persistent LTβR signaling is linked to tumor growth and the development of blood vessels that feed the tumor.