After receiving his B.S. in biology from Haverford College, David Lewinsohn attended Stanford University School of Medicine. In 1989 he received his Ph.D. in cancer biology and received his M.D. the same year. Dr. Lewinsohn was a Fellow of Pulmonary and Critical Care Medicine at the University of Washington, Seattle, WA, from 1993-1996, and a senior fellow and acting instructor from 1996-1998. During 1996-1998 he was also an investigator at the Infectious Disease Research Institute in Seattle, WA. At present, he is an Associate Professor in Pulmonary and Critical Care Medicine at the Portland VA Medical Center, an adjunct Associate Professor at the OHSU Department of Molecular Microbiology and Immunology, and an Associate Scientist at the Vaccine and Gene Therapy Institute.
Tuberculosis is the leading single cause of infectious disease mortality worldwide. Immunity to tuberculosis depends upon the cellular immune system. Hence, developing an improved vaccine will require an understanding of the mechanisms by which T cells recognize cells infected with the bacterium Mycobacterium tuberculosis (Mtb). Because Mtb is a facultative intracellular pathogen, cytotoxic cells may be important in the recognition and elimination of infected cells. The long term objectives of the laboratory are to investigate the basic cellular and molecular mechanisms of human CD8+ T cell responses to tuberculosis infection. There are several themes that guide the work of the laboratory.
First, how are antigens derived from Mtb processed and presented? Mtb lives in an arrested early endosomal compartment, normally thought to be a part of the MHC II compartment. My laboratory has focused on the hypothesis that the Mtb phagosome itself serves as an organelle in with processing and presentation can occur.
Second, what is the nature of these presentation molecules? T cells recognize antigen in the context of a "restricting molecule", so that understanding the nature of this restriction may aid in designing effective vaccine strategies. For HLA-Ia (HLA-A, B, &C) we have found that HLA-B predominates, and that the response is of high frequency and highly focused. However, we also find that non-classical (neither HLA-Ia nor CD1) responses are commonly found, particularly in those without evidence of prior exposure to Mtb. Here we have focused our efforts on the non-classical molecule HLA-E. Additionally, we have recently found the MR1-restricted Mucocsa Invariant T Cells (MAIT) to comprise many of these cells. Because these cells reside in the lung and gut, are present at high frequency, recognize Mtb-infected epithelial cells, and are “pre-armed” with cytokine and cytolytic potential, these cells are poised to play critical role in the early responses to Mtb. Efforts are currently underway to define the molecular basis for both HLA-E and MR1 dependent recognition of Mtb infected cells.
Finally, antigens are the language of immunology. Consequently, we are performing a genome wide analysis of those antigens presented during the course of infection with Mtb. Clinical validation of these antigens takes place in collaboration with the TB Research Unit (Case Western Reserve University) and Makerere University (Kampala, Uganda).It is hoped that this work may aid development of improved diagnostics and vaccines against tuberculosis.
1. Grotzke, J.E., M.J. Harriff, A.C. Siler, D. Nolt, J. Delepine, D.A. Lewinsohn, and D.M. Lewinsohn. 2009. The Mycobacterium tuberculosis phagosome is a HLA-I processing competent organelle. PLoS Pathog 5:e1000374.
2. Lewinsohn, D.A., and D.M. Lewinsohn. 2008. Immunologic susceptibility of young children to Mycobacterium tuberculosis. Pediatr Res 63:115.
3. Gold, M.C., H.D. Ehlinger, M.S. Cook, S.K. Smyk-Pearson, P.T. Wille, R.M. Ungerleider, D.A. Lewinsohn, and D.M. Lewinsohn. 2008. Human innate Mycobacterium tuberculosis-reactive alphabetaTCR+ thymocytes. PLoS Pathog 4:e39.
4. Lewinsohn, D.A., E. Winata, G.M. Swarbrick, K.E. Tanner, M.S. Cook, M.D. Null, M.E. Cansler, A. Sette, J. Sidney, and D.M. Lewinsohn. 2007. Immunodominant tuberculosis CD8 antigens preferentially restricted by HLA-B. PLoS Pathog 3:1240-1249.
5. Gold, M.C., T.L. Robinson, M.S. Cook, L.K. Byrd, H.D. Ehlinger, D.M. Lewinsohn, and D.A. Lewinsohn. 2007. Human neonatal dendritic cells are competent in MHC class I antigen processing and presentation. PLoS One 2:e957.
6. Lewinsohn, D.M., J.E. Grotzke, A.S. Heinzel, L. Zhu, P.J. Ovendale, M. Johnson, and M.R. Alderson. 2006. Secreted proteins from Mycobacterium tuberculosis gain access to the cytosolic MHC class-I antigen-processing pathway. J Immunol 177:437-442.
7. Grotzke, J.E., and D.M. Lewinsohn. 2005. Role of CD8+ T lymphocytes in control of Mycobacterium tuberculosis infection. Microbes Infect 7:776-788.
8. Rosen, H.R., D.J. Hinrichs, R.L. Leistikow, G. Callender, A.M. Wertheimer, M.I. Nishimura, and D.M. Lewinsohn. 2004. Cutting edge: identification of hepatitis C virus-specific CD8+ T cells restricted by donor HLA alleles following liver transplantation. J Immunol 173:5355-5359.
9. Lewinsohn, D.A., A.S. Heinzel, J.M. Gardner, L. Zhu, M.R. Alderson, and D.M. Lewinsohn. 2003. Mycobacterium tuberculosis-specific CD8+ T cells preferentially recognize heavily infected cells. Am J Respir Crit Care Med 168:1346-1352.
10. Heinzel, A.S., J.E. Grotzke, R.A. Lines, D.A. Lewinsohn, A.L. McNabb, D.N. Streblow, V.M. Braud, H.J. Grieser, J.T. Belisle, and D.M. Lewinsohn. 2002. HLA-E-dependent presentation of Mtb-derived antigen to human CD8+ T cells. J Exp Med 196:1473-1481.
11. Lewinsohn, D.M., M.R. Alderson, A.L. Briden, S.R. Riddell, S.G. Reed, and K.H. Grabstein. 1998. Characterization of human CD8+ T cells reactive with Mycobacterium tuberculosis-infected antigen-presenting cells. J Exp Med 187:1633-1640.
A more complete listing of publications by Dr. Lewinsohn is available from the National Library of Medicine [PubMed]
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