LYMPHOTOXIN-ALPHA-DEFICIENT AND TNF RECEPTOR-I-DEFICIENT MICE DEFINE DEVELOPMENTAL AND FUNCTIONAL-CHARACTERISTICS OF GERMINAL-CENTERS

Mice deficient in LT alpha (LT alpha(-/-)) lack lymph nodes and Peyer' s patches. This action of LT alpha in lymph node organogenesis appears to be mediated by the membrane form of LT using a mechanism independe nt of TNF receptor I (TNFR-I) or II (TNFR-II). In contrast, normal Pey er's patch development appears to require both LT alpha and TNFR-I, wi th TNFR-I-/- mice showing hypoplastic Peyer's patch structures. LT alp ha(-/-) mice also fail to support the normal segregation of T-cell and B-cell zones within the splenic white pulp. Again, this occurs via a mechanism independent of TNFR-I or TNFR-II. Additionally, follicular d endritic cell (FDC) clusters or germinal centers fail to develop in th e spleen of LT alpha(-/-) animals. Mice deficient in either TNF alpha or TNFR-I also fail to develop splenic FDC clusters and germinal cente rs. indicating that signaling by both LT alpha and TNF alpha is requir ed for development of these specialized lymphoid tissue structures. Fi nally, the splenic white pulp areas in LT alpha(-/-) mice lack the mar ginal zone of monoclonal antibody MOMA-1-staining metallophilic macrop hages, whereas TNFR-I-deficient mice have preserved MOMA-1 staining. T hus, certain actions of LT alpha to regulate spleen white pulp archite cture are mediated by receptors other than TNFR-I, most Likely by the LT beta R or a closely related receptor. We tested whether germinal ce nters are essential for maturation of T-cell-dependent antibody respon ses, When LT alpha(-/-) mice were immunized with low doses of NP-ovalb umin (NP-OVA) adsorbed to alum, there was dramatically impaired produc tion of high affinity anti-NP IgG; however, after immunization with hi gh doses of NP-OVA adsorbed to alum, LT alpha(-/-) mice mounted a high affinity NP-specific serum IgG response similar to wild-type mice, al l in the absence of germinal centers or clustered FDC. Thus, although germinal centers enhance the processes required for maturation of the humoral immune response, the mechanisms responsible for affinity matur ation are not absolutely dependent on the presence of germinal centers .