Abnormal development of secondary lymphoid tissues in lymphotoxin beta-deficient mice - PubMed (original) (raw)

Abnormal development of secondary lymphoid tissues in lymphotoxin beta-deficient mice

M B Alimzhanov et al. Proc Natl Acad Sci U S A. 1997.

Abstract

The tumor necrosis factor (TNF) family cytokines lymphotoxin (LT) alpha and LTbeta form heterotrimers that are expressed on the surface of activated lymphocytes and natural killer cells; LTalpha homotrimers can be secreted as well. Mice with a disrupted LTalpha gene lack lymph nodes (LN), Peyer's patches (PP), and follicular dendritic cell (FDC) networks and reveal profound defects of the splenic architecture. However, it is unclear which of these abnormalities is the result of the absence in LTalpha homotrimers or LTalphabeta heterotrimers. To distinguish between these two possibilities, a mouse strain deficient in LTbeta was created employing Cre/loxP-mediated gene targeting. Mice deficient in LTbeta reveal severe defects in organogenesis of the lymphoid system similar to those of LTalpha-/- mice, except that mesenteric and cervical LN are present in most LTbeta-deficient mice. Both LTbeta- and LTalpha-deficient mice show significant lymphocytosis in the circulation and peritoneal cavity and lymphocytic infiltrations in lungs and liver. After immunization, PNA-positive B cell clusters were detected in the splenic white pulp of LTbeta-deficient mice, but FDC networks were severely underdeveloped. Collectively, these results indicate that LTalpha can signal independently from LTbeta in the formation of PNA-positive foci in the spleen, and especially in the development of mesenteric and cervical LN.

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Figures

Figure 1

Figure 1

Generation of LTβΔ/Δ mice. (A) Targeting strategy used for inactivation of the mouse LTβ gene. B, _Bam_HI; H, _Hin_dIII; K, _Kpn_I; M, _Mlu_I; N, _Nde_I. (B) Southern blot analysis of genomic DNA from targeted ES cells and from mouse tail biopsies. (C) Northern blot analysis of total RNA extracted from thymocytes or ConA-activated splenocytes derived from LTβ+/+, LTβ+/Δ, and LTβΔ/Δ mice. 18S RNA was stained with methylene blue (loading control).

Figure 2

Figure 2

Peripheral lymphoid organs in LTβΔ/Δ mice as compared with LTα−/− mice (11). (A) Defective spleen organization in LTβΔ/Δ and LTα−/− mice. Splenic cryosections of 6- to 8-week-old mice were processed to detect the distribution of T cells (CD3, blue) and B cells (B220, red) or metallophilic macrophages (MOMA-1). Original magnification, ×100. (B) Immunohistological analysis of mesenteric LN from LTβΔ/Δ mice. Serial sections were labeled with anti-CD3 (blue)/anti-B220 (red), anti-MOMA-1, anti-MAdCAM-1, or anti-FDC-M1 antibody.

Figure 3

Figure 3

Lymphocytic infiltrations in lungs of LTβΔ/Δ and LTα−/− mice. Serial sections of frozen organs from 8-week-old mice were labeled with anti-CD4, anti-CD8, or anti-B220 antibody. Original magnification, ×100.

Figure 4

Figure 4

Impaired FDC network development and germinal center formation in spleens of LTβΔ/Δ and LTα−/− mice. Eight-week-old mice were immunized intraperitoneally with SRBC, and 10 days later spleens were removed. Immunofluorescence microscopy was performed on cryosections of spleens to detect formation of germinal centers (PNA-FITC IgM-Texas Red) and development of FDC networks (FDC-M2). Original magnification, ×100.

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