LYMPHOTOXIN-ALPHA (LT-ALPHA) SUPPORTS DEVELOPMENT OF SPLENIC FOLLICULAR STRUCTURE THAT IS REQUIRED FOR IGG RESPONSES

LT alpha-deficient (LT alpha(-/-)) mice show altered splenic microarch itecture. This includes loss of normal B cell-T cell compartmentalizat ion, of follicular dendritic cell (FDC) clusters, and of ability to fo rm 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 primacy or secondary responses, demonstrating failure o f Ig class switching. This inability to switch to IgG could have been due to the altered splenic microarchitecture in these mice. Alternativ ely, it could have been due directly to a requirement for LT alpha exp ression by lymphocytes cooperating in the antibody response. To invest igate this, we performed reciprocal spleen cell transfers. When irradi ated LT alpha(-/-) mice were reconstituted with wild-type splenocytes and immunized immediately with SRBC, splenic microarchitecture remaine d disturbed and there was no IgG response. In contrast, when irradiate d wild-type animals received splenocytes from LT alpha(-/-) mice, foll icle structure and a strong IgG response were retained. These data ind icate that LT alpha-deficient B cells and T cells have no intrinsic de fect in ability to generate an IgG response. Rather, the altered micro environment characteristic of LT alpha(-/-) mice appears to result in impaired ability to switch to a productive IgG response. To investigat e whether prolonged expression of LT alpha could alter the structure a nd function of spleen follicles, reciprocal bane marrow (BM) transplan tation tvas performed. Six weeks after reconstitution of LT alpha(-/-) mice with wild-type BM, spleen follicle structure was partially resto red, with return of FDC clusters and GC. B cell/T cell compartmentaliz ation remained abnormal and white pulp zones were small. This was acco mpanied 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 an d T cell zones were largely retained. Thus, defective IgG production i s not absolutely associated with abnormal B cell and T cell compartmen talization. Rather, expression of LT alpha supports the maturation of spleen follicle structure, including the development and maintenance o f FDC clusters, which supports Ig class switching and an effective IgG response.