Linda F. Thompson, Ph.D.
Putnam City Schools Distinguished Chair in Cancer Research
Adjunct Professor, Department of Microbiology & Immunology, University of Oklahoma Health Sciences Center
In my lab, we are interested in human diseases caused by mutations in DNA. We are intrigued by the idea that some diseases, such as cystic fibrosis and hemophilia, can be completely explained by a single change (i.e., mutation) in one of DNA’s thousands of bases. This single base change can lead to a change in a single amino acid in a protein such as an enzyme, and this amino acid change can make the protein non-functional and cause disease. Our lab studies a form of severe combined immunodeficiency caused by a mutation in the gene adenosine deaminase (ADA). Children who inherit mutations in the ADA gene lack both T and B lymphocytes, two of the most important cell types in the immune system, and will die of an infection if they do not receive a bone marrow transplant. This disease is difficult to study in the laboratory because the patients are very rare and they lack the very cells (lymphocytes) whose properties need to be investigated. Therefore, we developed a model system using fetal thymic tissue from mice and a drug that can inhibit the enzyme activity of ADA and mimic the disease. We are now extending our studies using human thymic tissue that must be removed in certain cardiac surgeries so that the surgeon can have access to the heart.
Another area of interest for us is a second enzyme called ecto-5′-nucleotidase or 5′-NT. This enzyme produces adenosine, a substance that can bind to cell surface adenosine receptors found on almost all cells. Adenosine receptors regulate a variety of important physiological processes, such as nerve transmission, heart rate, kidney function, smooth muscle contraction, and inflammation. My colleagues and I have engineered a strain of mice that lack 5′-NT and are using these mice to understand the function of 5′-NT. Work in my lab centers on the ability of adenosine produced by 5′-NT to modulate various types of inflammatory responses. However, we have shared our mice with many other groups of scientists all over the United States and even in Germany and China so that investigators with expertise in a wide variety of fields can have access to this unique tool.
B.S., University of Michigan, Ann Arbor, 1968
M.S., University of Michigan, Ann Arbor, 1971
Ph.D., University of Michigan, Ann Arbor, 1973
Honors and Awards
1965-1968 Michigan Non-resident Alumni Fund Scholarship
1969-1970 National Science Foundation Traineeship
1972 Phi Lambda Upsilon
1973 Sigma Xi
1977-1980 Arthritis Foundation Postdoctoral Fellowship
2001 Putnam City Schools Distinguished Chair in Cancer Research
2007 Edward L. and Thelma Gaylord Prize for Scientific Achievement
Serves as a regular reviewer for the Journal of Immunology; and serves as a Department of Defense Breast Cancer Research Program Reviewer.
Scientific Advisory Board of Intergenetics
Ad hoc reviewer for a variety of NIH Special Emphasis Panels.
American Association for the Advancement of Science
American Association of Immunologists
American Federation for Medical Research
Clinical Immunology Society
Joined OMRF Scientific Staff in 1989.
Research in my laboratory concerns the role of ecto-5′-nucleotidase (CD73), a purine metabolizing enzyme, in generating adenosine for adenosine receptor signaling. Ecto-5′-nucleotidase is a glycosyl phosphatidylinositol (GPI)-anchored enzyme that catalyzes the dephosphorylation of extracellular AMP to adenosine. Adenosine receptors are seven transmembrane spanning G-protein coupled receptors that regulate many important aspects of physiology. We are using CD73-deficient mice, created in our lab, to learn more about the ability of CD73 to generate adenosine for adenosine receptor signaling. CD73-/- mice appear healthy and reproduce normally but show exaggerated responses to a variety of inflammatory stimuli. For example, they exhibit a vascular leak syndrome characterized by neutrophil accumulation in tissues, especially the lung, when exposed to hypoxia. They also show elevated cytokine responses in experimental models of colitis, sepsis, and pulmonary inflammation and fibrosis. CD73-deficient mice exhibit increased lymphocyte migration to the draining lymph nodes after exposure to an inflammatory stimulus. Surprisingly, CD73-deficient mice are resistant to the development of experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. The development of EAE depends upon the ability of pathogentic T cells to enter the central nervous system. These findings suggest that CD73-generated adenosine plays an important role in regulating leukocyte migration across endothelial and epithelial barriers in a variety of physiological or pathological settings. Future studies will investigate the mechanism by which adenosine either inhibits or promotes leukocyte trafficking under specific experimental circumstances. We are also investigating the importance of the GPI anchor of CD73 in its ability to provide adenosine for adenosine receptor signaling using newly-created transgenic mice expressing CD73 with a conventional transmembrane anchor.
We are also participants in a multi-investigator project to understand why some lupus patients fail to make adequate responses to immunization with the influenza vaccine. In collaboration with Drs. Judith James, Sherry Crowe, Michelle Joachims, Gillian Air (at OUHSC), Patrick Wilson (at University of Chicago), Mark Coggeshall, and Joel Guthridge, we are studying various aspects of the immune response to influenza vaccination in lupus patients and healthy matched control subjects. The role of my lab is to investigate the cellular immune response. Our study is part of a larger NIH Biodefense program to improve vaccine responses in immunocompromised individuals including the very young, the elderly, patients receiving chemotherapy, organ transplant recipients, and patients with autoimmune diseases.
Thompson LF, Tsukamoto H, Chernogorova P, Zeiser R. A delicate balance: CD73-generated adenosine limits the severity of graft vs. host disease but also constrains the allogeneic graft vs. tumor effect. Oncoimmunology 2:e22107, 2013. [Abstract]
Stagg J, Thompson LF, Dwyer KM. Ectonucleotidases in cancer and inflammation. J Biomed Biotechnol 2012:951423, 2012. [Abstract]
* Popova L, Smith K, West AH, Wilson PC, James JA, Thompson LF, Air GM. Immunodominance of antigenic Site B over Site A of Hemagglutinin of recent H3N2 influenza viruses. PLoS One 7:e41895, 2012. [Abstract]
Takedachi M, Oohara H, Smith BJ, Iyama M, Kobashi M, Maeda K, Long CL, Humphrey MB, Stoecker BJ, Toyosawa S, Thompson LF, Murakami S. CD73-generated adenosine promotes osteoblast differentiation. J Cell Physiol 227:2622-2631, 2012. [Abstract]
* Air GM, Feng J, Chen T, Joachims ML, James JA, Thompson LF. Individual Antibody and T Cell Responses to Vaccination and Infection with the 2009 Pandemic Swine-Origin H1N1 Influenza Virus. J Clin Immunol 2011. [Abstract] EPub
* Crowe SR, Merrill JT, Vista ES, Dedeke AB, Thompson DM, Stewart S, Guthridge JM, Niewold TB, Franek BS, Air GM, Thompson LF, James JA. Influenza vaccination responses in human systemic lupus erythematosus: impact of clinical and demographic features. Arthritis Rheum 63:2396-2406, 2011. [Abstract]
Wang L, Fan J, Thompson LF, Zhang Y, Shin T, Curiel TJ, Zhang B. CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice. J Clin Invest 121:2371-2382, 2011. [Abstract]
Ernst PB, Garrison JC, Thompson LF. Much ado about adenosine: adenosine synthesis and function in regulatory T cell biology. J Immunol 185:1993-1998, 2010. [Abstract]
Jin D, Fan J, Wang L, Thompson LF, Liu A, Daniel BJ, Shin T, Curiel TJ, Zhang B. CD73 on tumor cells impairs antitumor T-cell responses: a novel mechanism of tumor-induced immune suppression. Cancer Res 70:2245-2255, 2010. [Abstract]
Immunobiology and Cancer Research Program, MS 29
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, OK 73104
Phone: (405) 271-7235
Fax: (405) 271-7128