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1.0       Introduction

Lymphotoxin (LT) is a member of the tumour necrosis factor (TNF) superfamily that was originally thought to be functionally redundant to TNF, but these proteins were later found to have independent roles in driving lymphoid organogenesis. More recently, LT mediated signalling has been shown to actively contribute to effector immune responses. LT regulates dendritic cell and CD4+ T cell homeostasis in the steady state and determines the functions of these cells during pathogenic challenges. The LT receptor pathway is essential for controlling pathogens and even contributes to the regulation of the intestinal microbiota, with recent data suggesting that LT induced changes in the microbiota promote metabolic disease. In this Review, we discuss these newly defined roles for LT, with a particular focus on how the LT receptor pathway regulates innate and adaptive immune responses to microorganisms (Uphadhyay and Fu 2013).

Lymphotoxin-α (LTα; also known as TNFSF1) is a member of the tumour necrosis factor (TNF) super-family and was originally identified as a product of lymphocytes that was capable of exerting cytotoxic effects on tumour cells in vitro (hence the name lymphotoxin) (Eberl 2012). LTα forms a homotrimer that binds to herpes virus entry mediator (HVEM; also known as TNFRSF14) with low affinity, and this has unknown biological effects. Homotrimers of LTα also bind to TNF receptor 1 (TNFR1; also known as TNFRSF1A) and TNFR2 (also known as TNFRSF1B) with high affinity, but they have a much less prominent role in driving TNFR signalling than does TNF itself (Ware et al., 1995, Josetowicz et al., 2012). It was later shown that LTα-mediated signalling is essential for the development of secondary lymphoid tissues, whereas TNF-mediated signalling alone has only a minor role in this process (Geuking et al., 2011, Fu and Chaplin 1999, Uphadhyay and Fu 2013).

LTα binds one or two membrane-associated LTβ to form LTα2β1 or LTα1β2 heterotrimers. The predominant LTα1β2 binds to LTβ receptor (LTβR) primarily expressed in epithelial and stromal cells. Most studies on LTβR signaling have focused on the organization, development, and maintenance of lymphoid tissues. However, the roles of LTβR signaling in the nervous system, particularly in neurogenesis, remain unknown (Xiao et al., 2018).

The lymphotoxin axis is important for the maintenance of several specialized lymphoid microenvironments in secondary lymphoid tissue. Lymphoid-tissue architecture is highly plastic and requires continual homeostatic signaling to maintain its basal functional state. The cellularity of lymph nodes in adult mice was reduced by systemic blockade of lymphotoxin-β receptor (LTβR) signaling with a soluble decoy receptor both in resting and reactive settings. This reduction in cellularity resulted from greatly impaired lymphocyte entry into lymph nodes due to decreased levels of peripheral lymph node addressin (PNAd) and MAd-CAM on high endothelial venules (HEV). LTβR signaling was required to maintain normal levels of RNA ex-pression of MAdCAM, and also of PNAd by regulating the expression of key enzymes and scaffold proteins required for its assembly. Thus, the homeostatic maintenance of functional HEV status in adult mice relies largely on LTβR signaling (Browning et al., 2005).

The tumor necrosis factor superfamily member (TNFSF) 14/LIGHT (homologous to lymphotoxins, exhibits inducible expression and competes with HSV glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes (Zhai et al., 1998) is a type II membrane protein. LIGHT is produced by activated T cells and can bind to lymphotoxin b receptor (LTbR) and HVEM, both of which belong to the TNF receptor superfamily (Aggarwal 2003). It is known that LIGHT-HVEM signaling regulates T-cell proliferation (Cheung 2009), while LIGHT-LTbR signaling induces apoptosis of cancer cells (Rooney et al., 2000) and organization and maintenance of lymphoid structures (Wang et al., 2002, Mikami et al., 2014).