The Lymphotoxin β Receptor Controls Organogenesis and Affinity Maturation in Peripheral Lymphoid Tissues

Abstract

Lymphotoxin beta receptor (LTbetaR)-/- mice were created by gene targeting. LTbetaR-/- mice lacked Peyer's patches, colon-associated lymphoid tissues, and all lymph nodes. Mucosa patrolling alphaEbeta7high integrin+ T cells were virtually absent. Spleens lost marginal zones; T/B cell segregation and follicular dendritic cell networks were absent. Peanut agglutinin+ cells were aberrantly detectable around central arterioles. In contrast to TNF receptor p55-/- mice, antibody affinity maturation was impaired. Since LTbetaR-/- mice exhibit distinct defects when compared to LTalpha-/- and LTbeta-/- mice, it is suggested that the LTbetaR integrates signals from other TNF family members. Thus, the LTbetaR proves pivotal for the ontogeny of the secondary lymphoid tissues. Furthermore, affinity maturation is dependent on LTalpha1beta2 rather than on LTalpha3.

The unexpected role of lymphotoxin β receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development

“…LTa À/À , LTb À/À and LTbR À/À mice display severe developmental defects in lymph node and Peyer's patch neogenesis, a disorganized lymphoid microarchitecture and lack of mature follicular dendritic cells (Pfeffer et al, 1993;De Togni et al, 1994;Koni et al, 1997;Futterer et al, 1998;Ngo et al, 1999). In addition, LTa À/À and LTbR À/À mice show inflammatory disorders in nonlymphoid organs (for example, lung, liver, kidney; (Fu et al, 1997(Fu et al, , 2000Fu and Chaplin, 1999;Chin et al, 2003).…”

Crosstalk via the NF-κB signaling system

“…Lymph nodes are located throughout the body to monitor the draining fluids and migrating lymphocytes for pathological changes (Lo et al, 2006;Mebius, 2003). The ltbr -/-mice demonstrated that lymphotoxin-β receptor (LTβR) signaling critically regulates lymph node formation (Futterer et al, 1998;Rennert et al, 1998). During early embryogenesis, membrane bound LTα 1 β 2 on the hematopoietically derived lymph tissue inducer cells (LTIC) signal through LTβR present on the stromal organizer cells to initiate lymph node development.…”

Targeting tumors with LIGHT to generate metastasis-clearing immunity

“…Studies in mutant mice and blocking experiments have identified a key requirement for TNF-family members, mainly lymphotoxin α1β2 (LTα1β2), and to some extent TNF, in the development and organization of lymph nodes and spleen microarchitecture [25][26][27][28]. Binding of LTα1β2 and TNF to their respective receptors, LTβR and TNFR1, induces the expression of chemokines and adhesion molecules, which directly mediate lymphocyte migration and homing [29].…”