In my lab, we are interested in human diseases caused by abnormal lymphocyte development or function. In the past, we have studied 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 cultured cells from the thymuses of children undergoing corrective cardiac surgery. The thymus is the organ where T cells develop. Thymus tissue must be removed in certain cardiac surgeries so that the surgeon can have access to the heart. The model systems that we developed to study ADA deficiency are now being used to study how T cells develop in a normal thymus. These studies are important because abnormal development of T cells in the thymus can lead to leukemia or lymphoma.
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 lacks 5′-NT and are using these mice to understand the function of this enzyme. Work in my lab centers on the ability of adenosine produced by 5′-NT to modulate various types of inflammatory responses. We have also discovered that 5’-NT contributes to the immunosuppressive environment surrounding many tumors. Inhibiting 5'-NT may be a new strategy for treating some types of cancers. We have shared our mice with many other groups of scientists all over the United States and even in Europe, Japan, China, and Australia so that investigators with expertise in a wide variety of fields can have access to this unique tool.
A third area of interest in my lab is autoimmunity. In the past, we studied the immune response of patients with lupus to immunization with the influenza vaccine. We were happy to find that most lupus patients did not experience a flare in their disease after vaccination. Together with other scientists at OMRF, we are now studying Sjögren’s Syndrome, an autoimmune disease that causes severe dry eyes and dry mouth.
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-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 studying the role of CD73 in contributing to an immunosuppressive tumor microenvironment.
My lab has had a long-standing interest in human lymphocyte development and the pathogenesis of human primary immunodeficiency diseases. We have been particularly intrigued by the question of how developing thymocytes “decide” whether to adopt the alpha/beta vs. gamma/delta T cell lineage. Recent observations demonstrate that the expression of CD73 marks those gamma/delta T cell receptor-expressing thymocytes that have committed to the gamma/delta lineage and can no longer adopt the alpha/beta fate. Experiments are ongoing to determine the mechanism by which CD73 appears to control the gamma/delta T cell fate.
We are also participants in a multi-investigator project to understand the pathogensis of the autoimmune disease Sjögren’s Syndrome (SS). Although SS is a systemic disease, its defining characteristics are dry eyes and dry mouth. Together with Dr. Darise Farris at OMRF, we are characterizing the T cells that infiltrate the minor salivary glands of patients with SS with the goal of determining the salivary gland antigen(s) which they recognize. We hope that this knowledge will lead to more rational treatments for SS patients.
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
2013 Merrick Award for Outstanding Medical Research
Section Editor for the Journal of Immunology
Ad hoc reviewer for a variety of NIH Study Sections
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
de Leve S, Wirsdörfer F, Cappuccini F, Schütze A, Meyer AV, Röck K, Thompson LF, Fischer JW, Stuschke M, Jendrossek V. Loss of CD73 prevents accumulation of alternatively activated macrophages and the formation of prefibrotic macrophage clusters in irradiated lungs. FASEB J. 2017 Jul; 31(7):2869-2880. PMID: 28325757
Joachims ML, Leehan KM, Lawrence C, Pelikan RC, Moore JS, Pan Z, Rasmussen A, Radfar L, Lewis DM, Grundahl KM, Kelly JA, Wiley GB, Shugay M, Chudakov DM, Lessard CJ, Stone DU, Scofield RH, Montgomery CG, Sivils KL, Thompson LF, Farris AD. Single-cell analysis of glandular T cell receptors in Sjögren's syndrome. JCI Insight. 2016 Jun 2;1(8). pii: e85609. [Abstract] PMCID: PMC4922426
Wirsdörfer F, de Leve S, Cappuccini F, Eldh T, Meyer AV, Gau E, Thompson LF, Chen NY, Karmouty-Quintana H, Fischer U, Kasper M, Klein D, Ritchey JW, Blackburn MR, Westendorf AM, Stuschke M, Jendrossek V. Extracellular adenosine production by ecto-5'-nucleotidase (CD73) enhances radiation-induced lung fibrosis. Cancer Res. 2016 Feb 26. pii: canres.2310.2015. [Epub ahead of print] [Abstract] PMID: 26921334
* Munroe ME, Vista ES, Guthridge JM, Thompson LF, Merrill JT, James JA. Pro-inflammatory adaptive cytokines and shed tumor necrosis factor receptors are elevated preceding systemic lupus erythematosus disease flare. Arthritis Rheumatol 66:1888-1899, 2014. [Abstract]
Coffey F, Lee SY, Buus TB, Lauritsen JP, Wong GW, Joachims ML, Thompson LF, Zuniga-Pflucker JC, Kappes DJ, and Wiest DL. The TCR ligand-inducible expression of CD73 marks γδ lineage commitment and a metastable intermediate in effector specification. J Exp Med. 211:329-43, 2014. [Abstract] PMCID:PMC3920555
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]
Tsukamoto H, Chernogorova P, Ayata K, Gerlach UV, Rughani A, Ritchey JW, Ganesan J, Follo M, Zeiser R, Thompson LF, Idzko M. Deficiency of CD73/ecto-5'-nucleotidase in mice enhances acute graft-versus-host disease. Blood. 119:4554-4564, 2012. [Abstract]
Blackburn MR, Thompson LF. Adenosine deaminase deficiency: unanticipated benefits from the study of a rare immunodeficiency. J Immunol. 188:933-935, 2012. [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]
Immunobiology and Cancer Research Program, MS 29
Oklahoma Medical Research Foundation
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Oklahoma City, OK 73104
Phone: (405) 271-7235
Fax: (405) 271-7128