Division of Molecular Medicine
College of Physicans & Surgeons of Columbia University
630 West 168th St., P & S 8-401, New York, N. Y., 10032
Integration of signaling pathways in lymphocyte activation and differentiation
Appropriate activation and differentiation of lymphocytes are critical for effective immune responses. In the case of humoral responses the activation of antigen-specific B cells is followed by their differentiation toward either a memory or a plasma cell. This stepwise progression through carefully timed developmental programs is normally guided by exposure to different stimuli, which need to be appropriately interpreted as lymphocytes proceed along their differentiation pathway. Although the early steps in lymphocyte activation have been extensively studied, the downstream effectors of these activation pathways and the processes by which these pathways integrate are not fully characterized. The goal of our laboratory is to understand the basic mechanisms employed by lymphocytes to integrate the information provided by different activation stimuli and to characterize the processes that allow lymphocytes to interpret this information in a “context-appropriate” manner.
To start dissecting these processes our laboratory has utilized, as a model system, the regulation of the B cell activation marker CD23, which is synergistically induced in response to CD40 and IL-4. Our studies have focused on IRF-4, a member of the interferon regulatory family of transcription factors shown by genetic studies to be essential for mature B cell function. Our studies can be summarized as follows:
1) We have determined that IRF-4 is a novel downstream component of both CD40 and IL-4 signal transduction pathways. Our studies suggest that IRF-4 participates in the formation of an “enhanceosome-like” complex, which controls CD23 expression. We believe that the assembly of these enhanceosome-like complexes may represent an ideal target for the final integration of signaling pathways. We further believe that IRF-4, via its modular structure, plays a critical role in mediating the assembly of lymphoid-specific “enhanceosome-like” complexes.
2) We have furthermore found that IRF-4 function can be modulated in a stage-specific manner by interaction with developmentally restricted sets of Krüppel zinc finger proteins. This may allow the expression of genes regulated by IRF-4 to be controlled in a stage-appropriate manner.
Present studies are focused on the characterization of the broader role of IRF-4 containing complexes in lymphocyte activation and differentiation utilizing both in vitro as well as in vivo systems.
Gupta S.,D. Xia, M. Jiang, S. Lee, and A. Pernis (1998) Signaling Pathways Mediated by the TNF- and Cytokine- Receptor Families Target a Common cis-Element of the IRF-1 Promoter. (Journal of Immunology, 161;5997-6004)
Gupta S., M. Jiang, and A. Pernis (1999) Interferon-? activates Stat6 and leads to the formation of Stat2:Stat6 complexes in B cells. (Journal of Immunology, 163; 3834-3841)
Gupta S., M. Jiang, A. Anthony, and A. Pernis (1999) Lineage-specific modulation of IL-4 signaling by IRF-4. (Journal of Experimental Medicine, 190; 1837-1848)
Gupta S., A. Anthony, and A. Pernis (2001) Stage-specific regulation of IRF-4 by Krüppel zinc finger proteins. (Journal of Immunology,166;6104-6111)
A. Pernis (2001) The role of IRF-4 in T and B cell activation and differentiation (Journal of Interferon and Cytokine Research, In press)