Optimal humoral responses depend on the activation of the appropriate antigen-specific B cells followed by their progression toward a fully differentiated phenotype, either a memory cell or a plasma cell. T cells play a key role in guiding this developmental program by providing both contact-dependent as well as soluble signals. Although the pivotal roles of the CD4O/CD4OL interaction as well as of IL-4 in this process are well recognized, the molecular mechanisms utilized by B cells to integrate these distinct classes of signals are poorly characterized. Utilizing the regulation of CD23 as a model system, we have identified IRF-4 as a novel component of both CD4O and IL-4 signal transduction pathways. We have furthermore found that IRF-4 function can be modulated in a stage-specific manner by interaction with developmentally restricted sets of Kruppel zinc finger proteins. We now propose that IRF-4 plays a crucial role in the integration of B cell activation pathways and that selective modulation of IRF-4 function by Kruppel zinc finger proteins is critical for regulating the developmental fate of activated B cells. To test these hypotheses we will: 1) Dissect the molecular mechanisms controlling IRF-4 function. 2) Characterize the role of IRF-4 in the regulation of additional CD4O/IL-4 target genes. 3) Investigate the role of the IRF-4/Kruppel interaction during terminal B cells differentiation. Completion of these studies will yield a better understanding of the molecular mechanisms utilized by lymphocytes to integrate distinct activation pathways. Moreover, knowledge of these pathways may allow for selective targeting of pathophysiological states characterized by inappropriate lymphocyte activation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Noel, Patricia
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
Internal Medicine/Medicine
Schools of Medicine
New York
United States
Zip Code
Stirzaker, R A; Biswas, P S; Gupta, S et al. (2012) Administration of fasudil, a ROCK inhibitor, attenuates disease in lupus-prone NZB/W F1 female mice. Lupus 21:656-61
Biswas, Partha S; Gupta, Sanjay; Stirzaker, Roslynn A et al. (2012) Dual regulation of IRF4 function in T and B cells is required for the coordination of T-B cell interactions and the prevention of autoimmunity. J Exp Med 209:581-96
Biswas, Partha S; Kang, Kyuho; Gupta, Sanjay et al. (2012) A murine autoimmune model of rheumatoid arthritis and systemic lupus erythematosus associated with deregulated production of IL-17 and IL-21. Methods Mol Biol 900:233-51
Biswas, Partha S; Gupta, Sanjay; Chang, Emily et al. (2011) Aberrant ROCK activation promotes the development of type I diabetes in NOD mice. Cell Immunol 266:111-5
Biswas, Partha S; Bhagat, Govind; Pernis, Alessandra B (2010) IRF4 and its regulators: evolving insights into the pathogenesis of inflammatory arthritis? Immunol Rev 233:79-96
Biswas, Partha S; Gupta, Sanjay; Chang, Emily et al. (2010) Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice. J Clin Invest 120:3280-95
Pernis, Alessandra B (2009) Rho GTPase-mediated pathways in mature CD4+ T cells. Autoimmun Rev 8:199-203
Chen, Qinzhong; Gupta, Sanjay; Pernis, Alessandra B (2009) Regulation of TLR4-mediated signaling by IBP/Def6, a novel activator of Rho GTPases. J Leukoc Biol 85:539-43
Pernis, A B (2009) Th17 cells in rheumatoid arthritis and systemic lupus erythematosus. J Intern Med 265:644-52
Chen, Qinzhong; Yang, Wen; Gupta, Sanjay et al. (2008) IRF-4-binding protein inhibits interleukin-17 and interleukin-21 production by controlling the activity of IRF-4 transcription factor. Immunity 29:899-911

Showing the most recent 10 out of 16 publications