David M. Center, M.D.
Gordon and Ruth Snider Professor of Pulmonary Medicine
Research Professor of Biochemistry
Chief, Pulmonary , Allergy and Critical Care Medicine
M.D. Boston University
Our laboratory studies the function of human CD4 and regulation of the cell cycle in T cells. Regarding the function of CD4, our laboratory discovered, cloned and characterized most of the biologic functions of Interleukin (IL-16). Since IL-16 utilizes CD4 as its receptor the discovery of IL-16 has led to a series of studies related to the functions of CD4 itself that are independent of MHCII restricted accessory activity. Using functional and microarray analyses we are exploring the signal transduction pathways associated with CD4 activation by IL 16 and the mechanisms of CD4′s functions as a chemotactic factor and growth factor receptor. Most recently this work has led to the discovery that IL-16-CD4 interaction results in selective chemotaxis of CD4+CD25+ Regulatory T cells; and that IL-16 is sufficient to induce differentiation of CD4+CD25lo T cells to express FoxP3 and acquire regulatory T cell function. One major part of the laboratory looks at the role IL-16 plays in development of regulatory T cells using knock-out and over expressing mice and animal models of Th1 and Th2 driven inflammation, including a model of airway inflammation.
The second major focus of the laboratory explores the ability of IL-16 to selectively activate CD4+ T regulatory cells to become responsive to IL-2 dependent cell proliferation. This work explores the use of IL-16 in CD4+ T regulatory cell immune reconstitution in individuals with severe asthma in which autologous T cells will be expanded ex vivo and re-infused into humans to inhibit airway inflammation in asthma.
The third focus of our laboratory relates to the study of a nuclear protein complex that targets histone deacetylases to specific transcription factors and represses transcription of a select family of genes involved in maintenance of T cell quiescence. The complex is regulated by T cell activation at the level of the scaffold protein as the enzymatically active components do not change with cell activation or during the cell cycle. Mutations and deletions in the scaffold protein, the precursor for IL-16 are common in T cell lymphomas and replacement of nuclear expression of the normal protein results in return to a normal cell cycle profile and loss of malignant characteristics. The current studies are exploring the mechanisms of regulation of Pro-IL-16 transcription itself as a regulatory element in T cell cycle and its role in the development of anergy. These studies include use of knock out and transgenic mice to study cell cycle related genes that lead to CD4+ T cell malignancies.
- Zhang, Y, D.M. Center, W.W. Cruikshank and H. Kornfeld. 1998. Processing and Activation of Interleukin 16 by Caspase 3. J.Biol. Chem. 273: 1144.
- Parada, N.A., W.W. Cruikshank, H. Kornfeld and D.M. Center. 1998. Synergistic Activation of CD4+ T cells by Interleukin 16 and Interleukin 2. J. Immunol. 160: 2115-2120.
- Wu, D.M.H., Zhang, Y., Parada, N.A., Kornfeld, H., Nicoll, J., Center, D.M., Cruikshank, W.W. 1999. Processing and Release of Interleukin-16 from CD4+ but not CD8+ T Cells is Activation Dependent. J. Immunol. 162: 1699.
- Center, D.M., Ryan, T.C., Kornfeld, H., Cruikshank, W.W. 2000. Interleukin 16: Implications for CD4 functions and HIV progression. Immunol. Today. 21:2273-2280.
- Center, D.M. Commentary: A role for the alveolar epithelium in recruitment of mononuclear cells into the lung. 2000. J. Clin. Invest. 106:741-743.
- Van Drenth C, Jenkins A, Ledwich L, Ryan TC, Mashikian MV, Brazer W, Center DM, Cruikshank WW. 2000. Desensitization of CXC chemokine receptor 4, mediated by IL-16/CD4, is independent of p56lck enzymatic activity. J. Immunol. 165: 6356-6363.
- Zhang, Y., Kornfeld, H., Cruikshank, W.W., Kim, S., Reardon, C.C., Center, D.M. 2001. Nuclear Translocation of the N-terminal Prodomain of Interleukin-16. J. Biol. Chem. 276: 1299-1303.To see additional publications by investigator click on any article and enter last name and initials in Query box.