After successful rearrangement of immunoglobulin heavy and light chain genes, B lymphocytes exit the bone marrow and enter the secondary lymphoid organs where they further differentiate into either marginal zone B cells (MZ B) or follicular B cells (FO B) cells, two mature B cell subsets that differ in surface phenotype, anatomic location and immunological function. Although B cell production rate, BCR specificity and BCR signaling strength have all been linked to development of MZ B cells, the molecular mechanism that controls MZ B cells development has not been fully elucidated. Notch signaling is critical for MZ B cell development. Genetic analysis has shown that MZ B cell development is severely impaired when either Notch2 or signaling molecules downstream of Notch signaling are deleted in mice. Notch signaling is found to be hyperactive in the MZ B cells and their precursors but not in the FO B cells. Mice expressing a constitutive active Notch transgene have a dramatically expanded MZ B cell population. Recent whole genome sequence analysis reveals that Notch2 and Notch1 are frequently mutated in MZ B cell derived lymphoma, indicating that hyperactive Notch signaling is critical for the tumorigenesis process. It has been shown that Notch signaling can be modulated intracellularly in other tissues. However, how Notch signaling is modulated in MZ B cells remains poorly understood. Interferon regulatory factor 4 (IRF4) is a member of IRF family of transcription factor. Previous works from us and others have shown that IRF4 is critical for B cell development and function. However, the role of IRF4 in MZ B cell development remains unclear. In this proposal, we will test the hypothesis that IRF4 is a negative regulator of Notch signaling that functions to limit MZ B cell development. We will test our hypotheses through the following specific aims:
aim #1 is to determine the effect of IRF4 on Notch signaling and development of MZ B cells;
and aim #2 is to elucidate the molecular mechanism by which IRF4 attenuates Notch signaling. Successful completion of this proposal could provide the molecular basis on the role of IRF4 not only in MZ B development but could also on the pathogenesis of MZ B cell derived lymphoma.

Public Health Relevance

MZ B cells reside in the marginal zone of spleen and play an important role in host defense against invading pathogens. Notch signaling is critical for MZ B cell development and mutation of Notch2 is found in over 20% of marginal zone derived B cell lymphoma. How Notch activity is regulated in developing B cells is poorly understood. Successful completion of this project will significantly advance our knowledge not only on the molecular mechanism that controls development of MZ B cells but also on the molecular pathogenesis of MZ B cell derived B cell malignancy.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Cellular and Molecular Immunology - B Study Section (CMIB)
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Ferguson, Stacy E
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University of Nebraska Medical Center
Schools of Medicine
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Shukla, Vipul; Shukla, Ashima; Joshi, Shantaram S et al. (2016) Interferon regulatory factor 4 attenuates Notch signaling to suppress the development of chronic lymphocytic leukemia. Oncotarget 7:41081-41094
Shukla, Vipul; Lu, Runqing (2014) IRF4 and IRF8: Governing the virtues of B Lymphocytes. Front Biol (Beijing) 9:269-282
Shukla, Vipul; Ma, Shibin; Hardy, Richard R et al. (2013) A role for IRF4 in the development of CLL. Blood 122:2848-55