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Vanderbilt-Ingram Cancer CenterVanderbilt-Ingram Cancer Center

Wasif N.  Khan

Wasif N. Khan, Ph.D.

Assistant Professor

Contact Information:

Vanderbilt University Medical Center
A-4207 Medical Center North
Nashville, TN 37232-2363

Research Specialty

Molecular Mechanisms of Lymphocyte Survival, Differentiation and Function in Health and Disease

Research Description

The focus of our research is to understand the molecular mechanisms of lymphocyte survival, differentiation and function in health and in autoimmune diseases as well as B-cell lymphomas. B-cell antigen receptor (BCR) and B cell activating factor receptor (BAFF-R or BR3) of the TNF-R family are essential regulators of B-lymphocyte development, survival and activation during immune responses. It is well established that immune responses are regulated and amplified by Toll-Like Receptors and CD40 in the face of challenges by bacteria and virus and other pathogens. Biochemical signals discharged from these receptors control B-cell physiological responses by inducing the functional expression of transcription factors and their downstream gene targets.

Our previous studies have shown that the development and function of B-lymphocytes can be regulated by several intracellular signaling mechanisms, including those involving the cytoplasmic protein tyrosine kinases (PTKs) Lyn, Syk, and Bruton's tyrosine kinase (Btk) appear. Gene targeted deletion of gene encoding Btk or naturally occurring mutations cause the B-cell deficiency diseases X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. These diseases are characterized by a reduction in mature B cells and impaired humoral immune responses. Thus, Btk is a key regulator of B cell development and function.

Using genetically manipulated mice for Btk and other signal transducers we have established an important role for these PTKs in the regulation of BCR- directed survival, proliferation and differentiation. For example, we have found that Btk-deficient mice display defects in splenic B lymphocyte survival and development from late immature or transitional 2 (T2) to follicular mature (Fo) B cells. We also found that Btk promotes B cell survival by inducing transcription of the pro-survival gene Bcl-xL in response to BCR stimulation. Furthermore, transcriptional activation of the Bcl-xL gene depends on the activation of transcription factor NF-?B. We have also shown that Btk couples NF-?B to the BCR via a mechanism involving I kappaB kinase (IKK) and that phospholipase C-?2 (PLC-?2) is an integral component of this Btk/NF-?B signaling axis.

PTKs are dynamically regulated by phosphorylation and other post-translational modifications, and the level of these modifications in a B-lymphocyte is constantly changing by the surrounding environment and invading pathogens. Therefore, current focus of our studies is to define biochemically and molecularly the mechanisms by which these PTKs, including Btk, regulate the biological responses of B-lymphocytes to immune regulatory receptors. We have recently found that Btk is involved in the mechanisms that control function of prosurvival BAFF-R and immune response regulator TLR. Further, the Btk/NF-?B signaling axis links BCR to the gene encoding p100 (NF-?B2), an integral component of the alternative NF-?B pathway. Moreover, Btk mediates NF-?B activation and increased production of p100/NF-?B2 following stimulation of BAFF-R, suggesting an important functional role for Btk in BAFF-dependent B cell responses.

These new findings illuminate new mechanisms by which Btk and other tyrosine kinases may transduce signals from BCR and BAFF-R to regulate B cell development, survival, and humoral immunity. We are now investigating whether the two NF-?B pathways are differentially activated at distinct stages of B cell maturation in the spleen and the pathophysiological significance of NF-?B pathways in development of the xid phenotype and development of B cell lymphoma. These investigations are designed to advance our understanding of normal B cell maturation/survival, B cell immunodeficiencies such as XLA and xid and B cell lymphomas at the molecular level to pave the way for drug discovery to cure these diseases.