Lymphotoxin-alpha-dependent spleen microenvironment supports the generation of memory B cells and is required for their subsequent antigen-induced activation.
Lymphotoxin alpha-deficient (LTalpha-/-) mice show dramatically reduced IgG responses after either primary or secondary immunizations with sheep red blood cells (SRBC). When splenocytes from SRBC-primed wild-type donor mice were infused into irradiated naive wild-type recipient mice, they generated a robust memory IgG response, but not when infused into LTalpha-/- recipients, indicating that the microenvironment that develops in LTalpha-/- mice is incompetent to support the activation of this memory response. When irradiated wild-type mice were reconstituted with splenocytes from primed LTalpha-/- donors and then challenged with the same immunizing Ag, no memory response was observed, indicating further that memory cells could not be generated in the LTalpha-/- environment. To address which lymphocyte subsets were impaired in the LTalpha-/- mice, we performed reconstitution experiments using a hapten/carrier system and T cells and B cells from different primed donors. There was no detectable defect in either the generation or expression of memory T cells from LTalpha-/- donors. In contrast, B cells were not primed for memory in the microenvironment of LTalpha-/- mice. Additionally, primed wild-type memory B cells could not express a memory IgG response in the LTalpha-/- microenvironment. Thus, splenic white pulp structure, which depends on the expression of LTalpha for its development and maintenance, is needed to support the generation of memory B cells and to permit existing memory B cells to express an isotype switched memory Ig response following antigenic challenge.
Fu
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YX
Departments of Laboratory Medicine/Pathology and Internal Medicine, and Howard Hughes Medical Institute and Center for Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. yfu@midway.uchicago.edu
Huang
G
G
Wang
Y
Y
Chaplin
D D
DD
D000818:Animals; D000941:Antigens / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D002449:Cell Aggregation / Q000276:immunology; D018858:Germinal Center / Q000166:cytology / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007156:Immunologic Memory / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics; D017710:Lymphocyte Transfusion; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019887:Peanut Agglutinin / Q000276:immunology; D013154:Spleen / Q000166:cytology* / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology
D000941:Antigens; D007074:Immunoglobulin G; D008233:Lymphotoxin-alpha; D019887:Peanut Agglutinin