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Absence of Mature Peripheral B Cell Populations in Mice with Concomitant Defects in B Cell Receptor and BAFF-R Signaling¹

Kristen L. Hoek,^2* Gianluca Carlesso,^23* Emily S. Clark, and Wasif N. Khan^4*

^*Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232; and Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136

Generation of mature B lymphocytes from early (T1) and late transitional (T2) precursors requires cooperative signaling through BCR and B cell-activating factor receptor 3 (BR3). Recent studies have shown that BCR signaling positively regulates NF-B2, suggesting BCR regulation of BR3 signaling. To investigate the significance of signal integration from BCR and BR3 in B cell development and function, we crossed Btk-deficient mice (btk^–/–), which are developmentally blocked between the T2 and the mature follicular B cell stage as a result of a partial defect in BCR signaling, and A/WySnJ mice, which possess a mutant BR3 defective in propagating intracellular signals that results in a severely reduced peripheral B cell compartment, although all B cell subsets are present in relatively normal ratios. A/WySnJ x btk^–/– mice display a B cell-autonomous defect, resulting in a developmental block at an earlier stage (T1) than either mutation alone, leading to the loss of mature splenic follicular and marginal zone B cells, as well as the loss of peritoneal B1 and B2 cell populations. The competence of the double mutant T1 B cells to respond to TLR4 and CD40 survival and activation signals is further attenuated compared with single mutations as evidenced by severely reduced humoral immune responses in vivo and proliferation in response to anti-IgM, LPS, and anti-CD40 stimulation in vitro. Thus, BCR and BR3 independently and in concert regulate the survival, differentiation, and function of all B cell populations at and beyond T1, earliest transitional stage.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study is supported in part by National Institutes of Health (NIH) Grant AI060729 (to W.N.K.). K.L.H. was supported in part by NIH Grants T32 HL69715-0 and F32-AI069770-01 and E.C. was supported in part by NIH Grant AI060729 and National Institute of Mental Health Grant 2R32 MH018917-21 for Biopsychosocial Research Training in Immunology and AIDS (to Neil Schneiderman, Department of Psychology, University of Miami, Miami, FL).

² K.L.H. and G.C. contributed equally to this work.

³ Current address: MedImmune, LLC. One MedImmune Way, Department of Respiratory Inflammation and Autoimmunity, Gaithersburg, MD 20878.

⁴ Address correspondence and reprint requests to Dr. Wasif N. Khan, Miller School of Medicine, University of Miami, 1600 Northwest 10th Avenue, Room 3347A, Rosenstiel Medical Sciences Building, Miami, FL 33136. E-mail address: wnkhan{at}med.miami.edu

⁵ Abbreviations used in this paper: BR3, B cell-activating factor 3; BAFF, B cell-activating factor belonging to the TNF family; BM, bone marrow; DNP, dinitrophenyl; Fo, follicular; GC, germinal center; HSA, human serum albumin; IKK, IB kinase; MZ, marginal zone; T1, early transitional stage; T2, late transitional stage; TD, T cell dependent; TI-I, T cell independent type 1; TNP, trinitrophenyl; wt, wild type.