Distinct Roles in Lymphoid Organogenesis for Lymphotoxins α and β Revealed in Lymphotoxin β–Deficient Mice

Abstract

Lymphotoxin alpha (LT alpha)-deficient mice revealed critical roles for LT alpha in lymphoid organogenesis, but it is not clear whether LT alpha functions through an LT alpha homotrimer (LT alpha3) or LT alpha/beta heterotrimers. We generated LTbeta-deficient mice and found them to lack Peyer's patches, peripheral lymph nodes, splenic germinal centers, and follicular dendritic cells. Unlike LT alpha-deficient mice, LT beta-deficient mice had cervical and mesenteric lymph nodes. Furthermore, the mesenteric lymph nodes had germinal center-like regions, although these structures appeared to lack follicular dendritic cells. The absence of cervical and mesenteric lymph nodes in LT alpha-deficient mice, and yet their presence in LT beta-deficient mice and in mice deficient in tumor necrosis factor receptor types I and II, suggest that LT alpha3 may signal via an as yet unidentified receptor.

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).…”

The Lymphotoxin β Receptor Is Critically Involved in Controlling Infections with the Intracellular Pathogens Mycobacterium tuberculosis and Listeria monocytogenes

“…LT␣ is biologically active both in its homotrimeric form and in heterotrimers along with LT␤ (LT␣ 1 ␤ 2 or LT␣ 2 ␤ 1 ) (16,21,23,24). To elucidate whether the homotrimeric and the heterotrimeric forms are involved in early resistance against pulmonary M. tuberculosis infection, bacterial multiplication was assessed in LT␣-and LT␤-KO mice 5 wk following intranasal challenge with ϳ500 CFU of strain H37Rv (Fig.…”

“…TNF 3 binds to the TNFRp55 and TNFRp75, whereas LT␣ 3 engages the TNFRp55, TNFRp75, and HVEM as homotrimer (16,20,22). In combination with the membranebound LT␤, LT␣ binds as the LT␣ 1 ␤ 2 heterotrimer to the LT␤R (16,21,23,24). TNF 3 , LT␣ 3 in concert with the TNFRp55, were shown to be of critical importance for the host defense against intracellularly replicating bacterial pathogens and for the formation and maintenance of fully differentiated granulomas (25)(26)(27)(28)(29)(30)(31).…”

Recent Progress in the Understanding of B‐Cell Functions in Autoimmunity

“…shown by the findings that LT-a [1], LT-b [2], TNF receptor-I [3], and TNF-a [4], knock-out (KO) mice all have abnormal splenic architecture, as do mice in which LT-a and/or LT-b signalling is disrupted [5±7]. Although it is still not exactly apparent why defects in signalling by TNF/LT create such disturbances in splenic architecture, it is intriguing that DC networks, conspicuous components of B-cell follicles, are not present in any of the different TNF/LT-KO mice [1±7].…”