Lymphotoxin alpha

Lymphotoxin α (LTα) and lymphotoxin β (LTβ) are members of the tumor necrosis factor superfamily (TNFSF), TNFSF1 and TNFSF3.

The lymphotoxin-alpha-beta complex (LT-alpha-beta) is located on the surface of activated lymphocytes and binds to a specific receptor, the LT-beta receptor (LT-beta R). In mice, signal transmission via this pathway is important for the development of lymph nodes and the organization of the spleen. LTα forms a soluble homotrimer (LTα3) that binds to tumor necrosis factor receptor 1 (TNFR1), TNFR2 and herpesvirus entry mediator (HVEM) (Mauri DN et al. 1998; Ware CF 2005). When co-expressed with lymphotoxin β (LTβ), which has a transmembrane domain, LTα forms a cell surface-bound heterotrimer (LTα1β2) that binds exclusively to the LTβ receptor (LTβR) (Crowe PD et al. 1994; Androlewicz MJ et al. 1992). LTββR has a second ligand, LIGHT, which also binds to HVEM. LTα1β2 is expressed by lymphoid cells such as activated T lymphocytes, B cells, natural killer (NK) cells and innate lymphoid cells type 3 (ILC3). LTβR is mainly expressed by stromal cells such as endothelial, mesenchymal and epithelial cells and by myeloid cells such as dendritic cells (DC) and macrophages. This specific expression pattern suggests that LTα1β2/LTβR interactions act as a communication signal between lymphocytes and stromal cells. These observations emphasize the dominant role of LTα1β2 in lymphoid organ development with the potential of LTα3 to promote cervical and mesenteric LN (Cyster JG 2014).

Beyond lymphoid organogenesis, lymphotoxin members have been shown to control the development and/or homeostasis of various immune cells as well as numerous aspects of the immune response (Koroleva EP et al. 2018). For example, LTβR promotes the development of NK and NKT cells and the homeostasis of CD8α-DC in lymphoid tissues (Wu Q et al. 1999). LTα1β2/LTβR interactions between CD4+ T helper cells and DC are necessary for the expansion of CD8+ T cells. LTα1β2/LTβR interactions between B cells and follicular DC enable the recruitment of DC and CD4+ T cells, which promotes the helper T cell response (Leon B et al. 2012). LT members are critical for germinal center formation and humoral immunity. LTβR signaling also controls the production of type I interferons in stromal cells and macrophages of lymphoid organs during viral infections. LTα1β2, which is expressed by ILC3, promotes the production of IL-22, which is required for the clearance of pathogens via the mucous membranes (Borelli A et al. 2021).

Lymphotoxin α (LTα), also known as TNFβ, was originally described in the 1960s as a cytotoxic factor produced by activated lymphocytes that can kill transformed cell lines. They got their different names from the evidence that these molecules can trigger the death of fibrosarcoma cells and are secreted by lymphocytes and monocytes respectively.

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