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Defective development and function of Bcl10-deficient follicular, marginal zone and B1 B cells

Abstract

Bcl10 is an intracellular protein essential for nuclear factor (NF)-κB activation after lymphocyte antigen receptor stimulation. Using knockout mice, we show that absence of Bcl10 impeded conversion from transitional type 2 to mature follicular B cells and caused substantial decreases in marginal zone and B1 B cells. Bcl10-deficient B cells showed no excessive apoptosis. However, both Bcl10-deficient follicular and marginal zone B cells failed to proliferate normally, although Bcl10-deficient marginal zone B cells uniquely failed to activate NF-κB efficiently after stimulation with lipopolysaccharide. Bcl10-deficient marginal zone B cells did not capture antigens, and Bcl10-deficient (Bcl10−/−) mice failed to initiate humoral responses, leading to an inability to clear blood-borne bacteria. Thus, Bcl10 is essential for the development of all mature B cell subsets.

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Figure 1: Targeted disruption of Bcl10 in mice.
Figure 2: Impaired maturation of follicular B cells in Bcl10-deficient mice.
Figure 3: Impaired development of marginal zone and B1 B cells in Bcl10-deficient mice.
Figure 4: Rudimentary marginal zone development in the spleens of Bcl10-deficient mice.
Figure 5: Impaired development of marginal zone B cells in Bcl10-deficient mice is B cell intrinsic.
Figure 6: Normal apoptosis in naive Bcl10-deficient follicular and marginal zone B cells, and inability of Bcl10-deficient marginal zone B cells to proliferate or activate NF-κB in response to LPS.
Figure 7: Inability of Bcl10-deficient marginal zone B cells to capture antigens, complete absence of humoral immune responses to T cell–independent– and T cell–dependent–specific antigens, and high susceptibility of Bcl10-deficient mice to bacterial infection.

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Acknowledgements

We acknowledge the technical support of J. Schuman and Y. Chen. We also thank J. Gatewood and R. Cross for their technical assistance with the FACS analysis. This work is supported in part by grant CA87064 (S.W.M.) and Cancer Center Support grant CA21765, both from the National Cancer Institute; by the American Lebanese Syrian Associated Charities, St. Jude Children's Research Hospital; by funds from the Blood Research Institute Foundation of the Blood Center of Southeastern Wisconsin (R.W. and D.W.); and by National Institutes of Health grants RO1 AI52327 (R.W.) and R01 HL073284 (D.W.).

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Correspondence to Stephan W Morris or Demin Wang.

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Xue, L., Morris, S., Orihuela, C. et al. Defective development and function of Bcl10-deficient follicular, marginal zone and B1 B cells. Nat Immunol 4, 857–865 (2003). https://doi.org/10.1038/ni963

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