Dorothy E. Lewis, Ph.D.
Adjunct Faculty, Department of Pathology & Immunology
Professor, Unversity of Texas Medical Branch at Galveston
Ph.D., University of Arizona
Postdoctoral, University of New Mexico
Research Interests: Mechanisms of Cell Death in HIV and HCV Pathogenesis and in the Growth of the Fetus
The main research in my lab stems from observations in HIV patients about cellular death mechanisms involving CD8+ T cells. Such cells are important in containing viral infections. In HIV, their increased death leads to loss of containment in vivo. Specifically, we found that monocytes are responsible for killing CD8+ T cells via interaction of B7 molecules with CD28 on the T cells. Such killing does not seem to involve conventional FAS or TNF-alpha signaling. This observation led to the discovery of an agonistic CD28 antibody which activates and kills subsets of human T cells and the T cell line, Jurkat. My lab is focusing on signaling mechanisms responsible for this unusual observation including, ZAP-70, PLCg, and NFkB translocation and kinetics.
In many chronic infections, as well as during aging, there is an accumulation of CD28null T cells. The mechanism responsible for the loss of CD28 is not clear; however, our work has shown that CD28 is downregulated by TNF-alpha and its own ligands, especially CD80. This has been observed both at a transcription level and on the surface. Interestingly, the agonistic CD28 antibody acts similarly to CD80 by inducing CD28 downregulation at the level of the promoter. This observation leads to a unifying hypothesis that as CD8+ T cells respond, they down-regulate CD28. In HIV, there is an increase in the death of these T cells, perhaps as a normal selection mechanism. Stimulated CD8+ T cells thus have 3 outcomes; upregulate CD28 and live, die via CD28 ligation or completely downregulate CD28 and live. This model would account for the accumulation of CD28null cells as we age.
The accumulation of CD28null T cells does not occur in mice, as the promoter is not regulated as it is in humans. To develop a model to study how CD28 is lost in vivo and how the loss affects the immune response, we are generating both BAC transgenic mice expressing human CD28 and a conditional transgenic mouse where we can turn off expression. With this mouse, we hope to study the role of CD28null cells during in vivo infection and aging.
In HCV infection, there is also increase T cell death in those that are more likely to respond to therapy with IFN-alpha and ribavirin.
Another focus of the lab concerns the molecular nature of fetal DNA in maternal circulation. Because the DNA appears to be contained in discrete bodies, our goal is to characterize the nature of the fetal DNA separate from maternal DNA, which is not in apoptotic bodies and use the knowledge to better enrich for fetal DNA to for genetic diagnosis. The hypothesis is that circulating apoptotic bodies are caused by failure to clear the many dying trophoblastic cells at the maternal/placental interface. In addition, such apoptosis increases during abnormal pregnancies, especially pre-eclampsia, the most common cause of morbidity in pregnant women.
Lewis, DE, DS Ng Tang, A Adu-Oppong, W Schober and JR Rodgers. Anergy and apoptosis in CD8+ T cells from HIV-infected individuals. J Immunol 153:412-420, 1994.
Lloyd, TE, L Yang, D Ng Tang, T Bennett, W Schober and DE Lewis. Regulation of CD28 costimulation in human CD8+ T cells. J Immunol 158:1551-1558, 1997.
Lewis, DE, DS Ng Tang, X Wang and C Kozinetz. Costimulatory pathways mediate monocyte-dependent lymphocyte apoptosis in HIV. Clin. Immunol. 90:302-312, 1999.
Lewis, DE, L Yang, W Luo, X Wang and JR Rodgers. HIV-specific T Lymphocyte precursors exist in a CD28-CD8+ T cell subset and increase with loss of CD4 T cells. AIDS 13:1029-1033, 1999.
X Wang and DE Lewis. CD86 expression correlates with amounts of HIV produced by macrophages in vitro. J Leuko Biol 69:405-415, 2001.
Paul, ME, WM Shearer, CA Kozinetz, DE Lewis. Comparison of CD8+ T-cell subsets in HIV-infected rapid progressor verses non-rapid progressor children. JACI 108:258-264, 2001.
Lewis, DE, M, Merched-Sauvage, JJ Goronzy, CM Weyand, AN Vallejo. Tumor necrosis factor- and CD80 modulate CD28 expression through a similar mechanism of T-cell receptor-independent inhibition of transcription. In press, J. Biol. Chem., May 2004.
Bischoff, FZ, MK Sinacori, DD Dang, D Marquez-Do, C Horne, DE Lewis, JL Simpson. Cell-free fetal DNA and intact fetal cells in maternal circulation: implications for first and second trimester noninvasive prenatal diagnosis. Human Reproduc 8:493-500, 2002.
- Bischoff FZ, DA Marquéz-Do, DI Martinez, D Dang, C Horne, D Lewis, JL Simpson. Intact fetal cell isolation from maternal blood: improved isolation using a simple whole blood progenitor cell enrichment approach (RosetteSep ). Clin Genetics 63:483-489, 2003.
For a complete list of Dr. Lewis' publications, visit PubMed.