Lymphotoxin-α (LTα) Supports Development of Splenic Follicular Structure That Is Required for IgG Responses

Abstract

LTα-deficient (LTα−/−) mice show altered splenic microarchitecture. This includes loss of normal B cell–T cell compartmentalization, of follicular dendritic cell (FDC) clusters, and of ability to form germinal centers (GC). LTα−/− mice immunized with sheep red blood cells (SRBC) produced high levels of antigen-specific IgM but no IgG in either primary or secondary responses, demonstrating failure of Ig class switching. This inability to switch to IgG could have been due to the altered splenic microarchitecture in these mice. Alternatively, it could have been due directly to a requirement for LTα expression by lymphocytes cooperating in the antibody response. To investigate this, we performed reciprocal spleen cell transfers. When irradiated LTα−/− mice were reconstituted with wild-type splenocytes and immunized immediately with SRBC, splenic microarchitecture remained disturbed and there was no IgG response. In contrast, when irradiated wild-type animals received splenocytes from LTα−/− mice, follicle structure and a strong IgG response were retained. These data indicate that LTα-deficient B cells and T cells have no intrinsic defect in ability to generate an IgG response. Rather, the altered microenvironment characteristic of LTα−/− mice appears to result in impaired ability to switch to a productive IgG response. To investigate whether prolonged expression of LTα could alter the structure and function of spleen follicles, reciprocal bone marrow (BM) transplantation was performed. Six weeks after reconstitution of LTα−/− mice with wild-type BM, spleen follicle structure was partially restored, with return of FDC clusters and GC. B cell/T cell compartmentalization remained abnormal and white pulp zones were small. This was accompanied by restoration of IgG response to SRBC. Reconstitution of wild-type mice with LTα−/− BM resulted in loss of FDC clusters and GC, and loss of the IgG response, although compartmentalized B cell and T cell zones were largely retained. Thus, defective IgG production is not absolutely associated with abnormal B cell and T cell compartmentalization. Rather, expression of LTα supports the maturation of spleen follicle structure, including the development and maintenance of FDC clusters, which supports Ig class switching and an effective IgG response.

Alternate Mucosal Immune System: Organized Peyer’s Patches Are Not Required for IgA Responses in the Gastrointestinal Tract

“…Further, LT-␣ Ϫ/Ϫ mice immunized with low doses of the T cell-dependent Ag 4-hydroxy-3-nitrophenyl-OVA adsorbed to alum exhibit impaired production of high affinity anti-4-hydroxy-3-nitrophenyl IgG Abs, whereas those LT-␣ Ϫ/Ϫ mice were able to generate high affinity anti-4-hydroxy-3-nitrophenyl IgG Abs after immunization with high doses of 4-hydroxy-3-nitrophenyl-OVA adsorbed to alum (42). Moreover, reconstitution of irradiated wild-type mice with bone marrow from LT-␣ Ϫ/Ϫ mice resulted in loss of FDC clusters and germinal centers and impairment of Ag-specific IgG responses (11). Taken together, these studies imply that impairment of serum IgG and mucosal IgA Ab responses in TNF/LT-␣ Ϫ/Ϫ mice may be due to a failure of Ig class switching and development of Ab-secreting cells.…”

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

“…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). Whether these inflammatory disorders are due to decreased expression of the autoimmune regulator, a key mediator of central tolerance for peripherally restricted antigens, in LTa À/À , LTb À/À and LTbR À/À mice (Chin et al, 2003) is challenged by various publications (Boehm et al, 2003;Rossi et al, 2007).…”

Regulation of Follicular Dendritic Cell Networks by Activated T Cells: The Role of CD137 Signaling

“…IgG anti-SRBC Abs were measured as previously described (30). In brief, 96-well Falcon plates (BD Biosciences) were coated with 150 l of 0.1% SRBC diluted in PBS.…”

“…Spleens were harvested, treated, and stained as previously described (30,31). In brief, spleens were harvested, embedded in OCT compound (Miles), and frozen at Ϫ80°C.…”