The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/6/2111/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 12, June 16, 1997 2111-2120

Articles

Lymphotoxin-{alpha} (LT{alpha}) Supports Development of Splenic Follicular Structure That Is Required for IgG Responses

Yang-Xin Fu*, Hector Molina{ddagger}, Mitsuru Matsumoto{ddagger}, Guangming Huang§, Jingjuan Min§, and David D. Chaplin{ddagger},§

From the * Department of Laboratory Medicine and Pathology, {ddagger} Department of Internal Medicine, and § Howard Hughes Medical Institute and Center for Immunology, Washington University School of Medicine, St. Louis, Missouri 63110

LT{alpha}-deficient (LT{alpha}–/–) 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). LT{alpha}–/– 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 LT{alpha} expression by lymphocytes cooperating in the antibody response. To investigate this, we performed reciprocal spleen cell transfers. When irradiated LT{alpha}–/– 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 LT{alpha}–/– mice, follicle structure and a strong IgG response were retained. These data indicate that LT{alpha}-deficient B cells and T cells have no intrinsic defect in ability to generate an IgG response. Rather, the altered microenvironment characteristic of LT{alpha}–/– mice appears to result in impaired ability to switch to a productive IgG response. To investigate whether prolonged expression of LT{alpha} could alter the structure and function of spleen follicles, reciprocal bone marrow (BM) transplantation was performed. Six weeks after reconstitution of LT{alpha}–/– 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 LT{alpha}–/– 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 LT{alpha} 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.

Address correspondence to David D. Chaplin, Washington University School of Medicine, 660 Euclid Ave., Box 8022, St. Louis, MO 63110.

1 Abbreviations used in this paper: AP, alkaline phosphatase; BM, bone marrow; FDC, follicular dendritic cells; LN, lymph nodes; LT{alpha}, lymphotoxin-{alpha}; NP-OVA, 4-hydroxy-3-nitrophenyl-ovalbumin; PP, Peyer's patches; RU, relative units.


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