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Lymphotoxin-alpha (LTalpha) supports development of splenic follicular structure that is required for IgG responses.

Fu YX, Molina H, Matsumoto M, Huang G, Min J, Chaplin DD - J. Exp. Med. (1997)

Bottom Line: This was accompanied by restoration of IgG response to SRBC.Thus, defective IgG production is not absolutely associated with abnormal B cell and T cell compartmentalization.Rather, expression of LTalpha 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine and Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

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

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Structure of spleen  follicles in irradiated mice reconstituted with wild-type or LTα−/−  splenocytes. After serum was  collected from mice shown in  Fig. 3, the spleens were harvested and frozen sections were  stained with anti-B220 (brown)  and anti-Thy1.2 (blue) to visualize the B cell and T cell zones  (A–D). Distinct B cell and T cell  zones were present in wild-type  mice that received splenocytes  from either normal (A) or LTα−/−  mice (C), whereas there was disturbed segregation of B cells and  T cells in LTα−/− mice that received splenocytes from either  normal (B) or LTα−/− mice (D).  FDC clusters were observed by  staining with the anti-CR1  monoclonal antibody 8C12  (blue) (E–H). FDC clusters were  retained in the spleen follicles of  wild-type mice that received  splenocytes from either wildtype (E) or LTα−/− mice (G),  whereas FDC clusters were absent in the spleens of LTα−/−  mice that received splenocytes  from either wild-type (F) or  LTα−/− mice (H).
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Figure 4: Structure of spleen follicles in irradiated mice reconstituted with wild-type or LTα−/− splenocytes. After serum was collected from mice shown in Fig. 3, the spleens were harvested and frozen sections were stained with anti-B220 (brown) and anti-Thy1.2 (blue) to visualize the B cell and T cell zones (A–D). Distinct B cell and T cell zones were present in wild-type mice that received splenocytes from either normal (A) or LTα−/− mice (C), whereas there was disturbed segregation of B cells and T cells in LTα−/− mice that received splenocytes from either normal (B) or LTα−/− mice (D). FDC clusters were observed by staining with the anti-CR1 monoclonal antibody 8C12 (blue) (E–H). FDC clusters were retained in the spleen follicles of wild-type mice that received splenocytes from either wildtype (E) or LTα−/− mice (G), whereas FDC clusters were absent in the spleens of LTα−/− mice that received splenocytes from either wild-type (F) or LTα−/− mice (H).

Mentions: To study the relationship between altered splenic microarchitecture and the ability to generate an anti-SRBC IgG response, mice that had been irradiated and treated with infusions of spleen cells were analyzed histologically. Wild-type mice reconstituted with either wild-type or LTα−/− splenocytes showed similarly segregated B cell and T cell zones (Fig. 4, A and C) and clusters of FDC (Fig. 4, E and G). This was associated with competence for antiSRBC IgG responses (see Fig. 3). In contrast, when irradiated LTα−/− mice were reconstituted with either wild-type or LTα−/− cells, B cell and T cell zones were disorganized (Fig. 4, B and D) without detectable FDC clusters (Fig. 4, F and H). This was associated with absence of anti-SRBC IgG responses (see Fig. 3). Production of antigen-specific IgM, however, was retained by all mice that received either wild-type or LTα−/− splenocytes, even in the context of disturbed splenic microarchitecture (data not shown).


Lymphotoxin-alpha (LTalpha) supports development of splenic follicular structure that is required for IgG responses.

Fu YX, Molina H, Matsumoto M, Huang G, Min J, Chaplin DD - J. Exp. Med. (1997)

Structure of spleen  follicles in irradiated mice reconstituted with wild-type or LTα−/−  splenocytes. After serum was  collected from mice shown in  Fig. 3, the spleens were harvested and frozen sections were  stained with anti-B220 (brown)  and anti-Thy1.2 (blue) to visualize the B cell and T cell zones  (A–D). Distinct B cell and T cell  zones were present in wild-type  mice that received splenocytes  from either normal (A) or LTα−/−  mice (C), whereas there was disturbed segregation of B cells and  T cells in LTα−/− mice that received splenocytes from either  normal (B) or LTα−/− mice (D).  FDC clusters were observed by  staining with the anti-CR1  monoclonal antibody 8C12  (blue) (E–H). FDC clusters were  retained in the spleen follicles of  wild-type mice that received  splenocytes from either wildtype (E) or LTα−/− mice (G),  whereas FDC clusters were absent in the spleens of LTα−/−  mice that received splenocytes  from either wild-type (F) or  LTα−/− mice (H).
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Figure 4: Structure of spleen follicles in irradiated mice reconstituted with wild-type or LTα−/− splenocytes. After serum was collected from mice shown in Fig. 3, the spleens were harvested and frozen sections were stained with anti-B220 (brown) and anti-Thy1.2 (blue) to visualize the B cell and T cell zones (A–D). Distinct B cell and T cell zones were present in wild-type mice that received splenocytes from either normal (A) or LTα−/− mice (C), whereas there was disturbed segregation of B cells and T cells in LTα−/− mice that received splenocytes from either normal (B) or LTα−/− mice (D). FDC clusters were observed by staining with the anti-CR1 monoclonal antibody 8C12 (blue) (E–H). FDC clusters were retained in the spleen follicles of wild-type mice that received splenocytes from either wildtype (E) or LTα−/− mice (G), whereas FDC clusters were absent in the spleens of LTα−/− mice that received splenocytes from either wild-type (F) or LTα−/− mice (H).
Mentions: To study the relationship between altered splenic microarchitecture and the ability to generate an anti-SRBC IgG response, mice that had been irradiated and treated with infusions of spleen cells were analyzed histologically. Wild-type mice reconstituted with either wild-type or LTα−/− splenocytes showed similarly segregated B cell and T cell zones (Fig. 4, A and C) and clusters of FDC (Fig. 4, E and G). This was associated with competence for antiSRBC IgG responses (see Fig. 3). In contrast, when irradiated LTα−/− mice were reconstituted with either wild-type or LTα−/− cells, B cell and T cell zones were disorganized (Fig. 4, B and D) without detectable FDC clusters (Fig. 4, F and H). This was associated with absence of anti-SRBC IgG responses (see Fig. 3). Production of antigen-specific IgM, however, was retained by all mice that received either wild-type or LTα−/− splenocytes, even in the context of disturbed splenic microarchitecture (data not shown).

Bottom Line: This was accompanied by restoration of IgG response to SRBC.Thus, defective IgG production is not absolutely associated with abnormal B cell and T cell compartmentalization.Rather, expression of LTalpha 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine and Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

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

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