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BAFF mediates survival of peripheral immature B lymphocytes.

Batten M, Groom J, Cachero TG, Qian F, Schneider P, Tschopp J, Browning JL, Mackay F - J. Exp. Med. (2000)

Bottom Line: Immature transitional B cells are targets for negative selection, a feature thought to promote self-tolerance.These findings support a model in which excessive BAFF-mediated survival of peripheral immature B cells contributes to the emergence and maturation of autoreactive B cells, skewed towards the MZ compartment.This work provides new clues on mechanisms regulating B cell maturation and tolerance.

View Article: PubMed Central - PubMed

Affiliation: Department of Arthritis and Inflammation, The Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.

ABSTRACT
B cell maturation is a very selective process that requires finely tuned differentiation and survival signals. B cell activation factor from the TNF family (BAFF) is a TNF family member that binds to B cells and potentiates B cell receptor (BCR)-mediated proliferation. A role for BAFF in B cell survival was suggested by the observation of reduced peripheral B cell numbers in mice treated with reagents blocking BAFF, and high Bcl-2 levels detected in B cells from BAFF transgenic (Tg) mice. We tested in vitro the survival effect of BAFF on lymphocytes derived from primary and secondary lymphoid organs. BAFF induced survival of a subset of splenic immature B cells, referred to as transitional type 2 (T2) B cells. BAFF treatment allowed T2 B cells to survive and differentiate into mature B cells in response to signals through the BCR. The T2 and the marginal zone (MZ) B cell compartments were particularly enlarged in BAFF Tg mice. Immature transitional B cells are targets for negative selection, a feature thought to promote self-tolerance. These findings support a model in which excessive BAFF-mediated survival of peripheral immature B cells contributes to the emergence and maturation of autoreactive B cells, skewed towards the MZ compartment. This work provides new clues on mechanisms regulating B cell maturation and tolerance.

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Immature B cells from splenocytes isolated from BAFF Tg mice survive in vitro in the absence of exogenous stimuli. Splenocytes isolated from control littermates were cultured for 72 h with or without BAFF as indicated. Splenocytes from BAFF Tg mice were plated in parallel in normal nonsupplemented medium. The R1 and R2 populations were analyzed by flow cytometry on FSC/SSC plots. The R1 and R2 gates are drawn on the plots. As in the legend to Fig. 3 A, expression of B220, IgM, IgD, HSA and L-selectin was analyzed on control freshly prepared splenocytes and BAFF Tg mice–derived splenocytes cultured for 72 h in normal medium. Histograms for fresh control splenocytes (gray line indicated with an arrowhead) and R2-gated BAFF Tg mice–cultured splenocytes (black line) are overlayed for comparison.
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Figure 6: Immature B cells from splenocytes isolated from BAFF Tg mice survive in vitro in the absence of exogenous stimuli. Splenocytes isolated from control littermates were cultured for 72 h with or without BAFF as indicated. Splenocytes from BAFF Tg mice were plated in parallel in normal nonsupplemented medium. The R1 and R2 populations were analyzed by flow cytometry on FSC/SSC plots. The R1 and R2 gates are drawn on the plots. As in the legend to Fig. 3 A, expression of B220, IgM, IgD, HSA and L-selectin was analyzed on control freshly prepared splenocytes and BAFF Tg mice–derived splenocytes cultured for 72 h in normal medium. Histograms for fresh control splenocytes (gray line indicated with an arrowhead) and R2-gated BAFF Tg mice–cultured splenocytes (black line) are overlayed for comparison.

Mentions: Splenocytes from control littermates were incubated in medium supplemented or not with BAFF. Splenocytes from BAFF Tg mice were cultured in nonsupplemented medium. As shown previously, survival in control splenocyte cultures is only apparent (R2 population) if BAFF is added to the culture (Fig. 6 A). In contrast, cultures of BAFF Tg–derived splenocytes in nonsupplemented medium gave rise after 72 h to a surviving population of cells in the R2 gate (Fig. 6 A). Surviving cells were mainly B cells with the same phenotype as surviving B cells after 72-h BAFF treatment of C57BL/6-derived splenic cells (Fig. 3 A), displaying IgMhi, IgDhi, B220hi, and HSAhi levels (Fig. 6 B), and therefore were mainly T2 B cells. These surviving cultured cells also displayed higher levels of L-selectin compared with fresh splenocytes from BAFF Tg mice (data not shown). T2 B cells from BAFF Tg mice, isolated by cell sorting, also survived for 72 h in vitro, indicating that the survival status of these cells is intrinsic rather than promoted by BAFF produced by splenic T cells in mixed cultures (data not shown). These results suggest that T2 B cells were “programmed/sensitized” by BAFF in vivo leading to extended, stimulation-independent survival of these cells ex vivo.


BAFF mediates survival of peripheral immature B lymphocytes.

Batten M, Groom J, Cachero TG, Qian F, Schneider P, Tschopp J, Browning JL, Mackay F - J. Exp. Med. (2000)

Immature B cells from splenocytes isolated from BAFF Tg mice survive in vitro in the absence of exogenous stimuli. Splenocytes isolated from control littermates were cultured for 72 h with or without BAFF as indicated. Splenocytes from BAFF Tg mice were plated in parallel in normal nonsupplemented medium. The R1 and R2 populations were analyzed by flow cytometry on FSC/SSC plots. The R1 and R2 gates are drawn on the plots. As in the legend to Fig. 3 A, expression of B220, IgM, IgD, HSA and L-selectin was analyzed on control freshly prepared splenocytes and BAFF Tg mice–derived splenocytes cultured for 72 h in normal medium. Histograms for fresh control splenocytes (gray line indicated with an arrowhead) and R2-gated BAFF Tg mice–cultured splenocytes (black line) are overlayed for comparison.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2193190&req=5

Figure 6: Immature B cells from splenocytes isolated from BAFF Tg mice survive in vitro in the absence of exogenous stimuli. Splenocytes isolated from control littermates were cultured for 72 h with or without BAFF as indicated. Splenocytes from BAFF Tg mice were plated in parallel in normal nonsupplemented medium. The R1 and R2 populations were analyzed by flow cytometry on FSC/SSC plots. The R1 and R2 gates are drawn on the plots. As in the legend to Fig. 3 A, expression of B220, IgM, IgD, HSA and L-selectin was analyzed on control freshly prepared splenocytes and BAFF Tg mice–derived splenocytes cultured for 72 h in normal medium. Histograms for fresh control splenocytes (gray line indicated with an arrowhead) and R2-gated BAFF Tg mice–cultured splenocytes (black line) are overlayed for comparison.
Mentions: Splenocytes from control littermates were incubated in medium supplemented or not with BAFF. Splenocytes from BAFF Tg mice were cultured in nonsupplemented medium. As shown previously, survival in control splenocyte cultures is only apparent (R2 population) if BAFF is added to the culture (Fig. 6 A). In contrast, cultures of BAFF Tg–derived splenocytes in nonsupplemented medium gave rise after 72 h to a surviving population of cells in the R2 gate (Fig. 6 A). Surviving cells were mainly B cells with the same phenotype as surviving B cells after 72-h BAFF treatment of C57BL/6-derived splenic cells (Fig. 3 A), displaying IgMhi, IgDhi, B220hi, and HSAhi levels (Fig. 6 B), and therefore were mainly T2 B cells. These surviving cultured cells also displayed higher levels of L-selectin compared with fresh splenocytes from BAFF Tg mice (data not shown). T2 B cells from BAFF Tg mice, isolated by cell sorting, also survived for 72 h in vitro, indicating that the survival status of these cells is intrinsic rather than promoted by BAFF produced by splenic T cells in mixed cultures (data not shown). These results suggest that T2 B cells were “programmed/sensitized” by BAFF in vivo leading to extended, stimulation-independent survival of these cells ex vivo.

Bottom Line: Immature transitional B cells are targets for negative selection, a feature thought to promote self-tolerance.These findings support a model in which excessive BAFF-mediated survival of peripheral immature B cells contributes to the emergence and maturation of autoreactive B cells, skewed towards the MZ compartment.This work provides new clues on mechanisms regulating B cell maturation and tolerance.

View Article: PubMed Central - PubMed

Affiliation: Department of Arthritis and Inflammation, The Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.

ABSTRACT
B cell maturation is a very selective process that requires finely tuned differentiation and survival signals. B cell activation factor from the TNF family (BAFF) is a TNF family member that binds to B cells and potentiates B cell receptor (BCR)-mediated proliferation. A role for BAFF in B cell survival was suggested by the observation of reduced peripheral B cell numbers in mice treated with reagents blocking BAFF, and high Bcl-2 levels detected in B cells from BAFF transgenic (Tg) mice. We tested in vitro the survival effect of BAFF on lymphocytes derived from primary and secondary lymphoid organs. BAFF induced survival of a subset of splenic immature B cells, referred to as transitional type 2 (T2) B cells. BAFF treatment allowed T2 B cells to survive and differentiate into mature B cells in response to signals through the BCR. The T2 and the marginal zone (MZ) B cell compartments were particularly enlarged in BAFF Tg mice. Immature transitional B cells are targets for negative selection, a feature thought to promote self-tolerance. These findings support a model in which excessive BAFF-mediated survival of peripheral immature B cells contributes to the emergence and maturation of autoreactive B cells, skewed towards the MZ compartment. This work provides new clues on mechanisms regulating B cell maturation and tolerance.

Show MeSH
Related in: MedlinePlus