Involvement of Distinct Cellular Compartments in the Abnormal Lymphoid Organogenesis in Lymphotoxin-α-Deficient Mice and Alymphoplasia (aly) Mice Defined by the Chimeric Analysis (original) (raw)

Abnormal development of secondary lymphoid tissues in lymphotoxin -deficient mice

Proceedings of the National Academy of Sciences, 1997

The tumor necrosis factor (TNF) family cytokines lymphotoxin (LT) ␣ and LT␤ form heterotrimers that are expressed on the surface of activated lymphocytes and natural killer cells; LT␣ homotrimers can be secreted as well. Mice with a disrupted LT␣ gene lack lymph nodes (LN), Peyer's patches (PP), and follicular dendritic cell (FDC) networks and reveal profound defects of the splenic architecture. However, it is unclear which of these abnormalities is the result of the absence in LT␣ homotrimers or LT␣␤ heterotrimers. To distinguish between these two possibilities, a mouse strain deficient in LT␤ was created employing Cre͞ loxP-mediated gene targeting. Mice deficient in LT␤ reveal severe defects in organogenesis of the lymphoid system similar to those of LT␣ ؊͞؊ mice, except that mesenteric and cervical LN are present in most LT␤-deficient mice. Both LT␤-and LT␣-deficient mice show significant lymphocytosis in the circulation and peritoneal cavity and lymphocytic infiltrations in lungs and liver. After immunization, PNA-positive B cell clusters were detected in the splenic white pulp of LT␤deficient mice, but FDC networks were severely underdeveloped. Collectively, these results indicate that LT␣ can signal independently from LT␤ in the formation of PNA-positive foci in the spleen, and especially in the development of mesenteric and cervical LN.

Abnormal development of secondary lymphoid tissues in lymphotoxin β-deficient mice

Proceedings of the National Academy of Sciences, 1997

The tumor necrosis factor (TNF) family cytokines lymphotoxin (LT) α and LTβ form heterotrimers that are expressed on the surface of activated lymphocytes and natural killer cells; LTα homotrimers can be secreted as well. Mice with a disrupted LTα gene lack lymph nodes (LN), Peyer’s patches (PP), and follicular dendritic cell (FDC) networks and reveal profound defects of the splenic architecture. However, it is unclear which of these abnormalities is the result of the absence in LTα homotrimers or LTαβ heterotrimers. To distinguish between these two possibilities, a mouse strain deficient in LTβ was created employing Cre/loxP-mediated gene targeting. Mice deficient in LTβ reveal severe defects in organogenesis of the lymphoid system similar to those of LTα−/−mice, except that mesenteric and cervical LN are present in most LTβ-deficient mice. Both LTβ- and LTα-deficient mice show significant lymphocytosis in the circulation and peritoneal cavity and lymphocytic infiltrations in lungs ...

Surface lymphotoxin α/β complex is required for the development of peripheral lymphoid organs

Journal of Experimental Medicine

For more than a decade, the biological roles and the apparent redundancy of the cytokines tumor necrosis factor (TNF) and lymphotoxin (LT) have been debated. LTo~ exists in its soluble form as a homotrimer, which like TNF only binds the TNF receptors, TNF-R55 or TNF-R75. The cell surface form of LT exists as a heteromer of LTot and LT[3 subunits and this complex specifically binds the LT[3 receptor (LT[3-R). To discriminate the functions of the LT and TNF systems, soluble LT[3-R-immunoglobulin (Ig) or TNF-RIg fusion proteins were introduced into embryonic circulation by injecting pregnant mice. Exposure to LT[3-RIg during gestation disrupted lymph node development and splenic architecture in the progeny indicating that both effects are mediated by the surface LTot/[3 complex. These data are the first to identify a cell surface ligand involved in immune organ morphogenesis. Moreover, they unambiguously discriminate the functions of the various TNF/LT ligands, provide a unique model to study compartmentalization of immune responses and illustrate the generic utility of receptor-Ig fusion proteins for dissecting/ordering ontogenetic events in the absence of genetic modifications.