Our studies of T cell activation led us to consider the role of physiologically abundant, """"""""nonimmune"""""""", small signaling molecules of extracellular ATP and adenosine and their receptors in lymphocyte development and effector functions. We found that extracellular adenosine suppresses all tested TCR-triggered effector functions of T lymphocytes, including TCR-triggered FasL mRNA upregulation in cytotoxic T lymphocytes (CTL), granule exocytosis, perforin-mediated cytotoxicity, and T cell proliferation. The """"""""memory"""""""" of T cells to exposure to adenosine was best explained by sustained increases in [cAMP]. Biochemical and genetic studies using A2a adenosine receptor deficient mice demonstrate that A2a receptors are solely responsible for adenosine-triggered cAMP increases and direct apoptotic effects of extracellular adenosine on T cells. It is established that effects of extracellular adenosine on T cells and thymocytes are mediated by adenosine receptor-mediated signaling rather than by intracellular toxicity of adenosine catabolites. The use of A2a receptor deficient mice also revealed the existence of A2a receptor independent pathway of effects of extracellular Adenosine on T cell activation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000626-09
Application #
6431610
Study Section
(LI)
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Thiel, Manfred; Caldwell, Charles C; Sitkovsky, Michail V (2003) The critical role of adenosine A2A receptors in downregulation of inflammation and immunity in the pathogenesis of infectious diseases. Microbes Infect 5:515-26
Lukashev, Dmitriy E; Caldwell, Charles C; Chen, Pearl et al. (2003) A serine/threonine phosphorylation site in the ectodomain of a T cell receptor beta chain is required for activation by superantigen. J Recept Signal Transduct Res 23:33-52
Kojima, Hidefumi; Sitkovsky, Michail V; Cascalho, Marilia (2003) HIF-1 alpha deficiency perturbs T and B cell functions. Curr Pharm Des 9:1827-32
Gomez, Gregorio; Sitkovsky, Michail V (2003) Targeting G protein-coupled A2a adenosine receptors to engineer inflammation in vivo. Int J Biochem Cell Biol 35:410-4
Sitkovsky, Michail V (2003) Use of the A(2A) adenosine receptor as a physiological immunosuppressor and to engineer inflammation in vivo. Biochem Pharmacol 65:493-501
Lukashev, Dmitriy E; Smith, Patrick T; Caldwell, Charles C et al. (2003) Analysis of A2a receptor-deficient mice reveals no significant compensatory increases in the expression of A2b, A1, and A3 adenosine receptors in lymphoid organs. Biochem Pharmacol 65:2081-90
Kojima, Hidefumi; Gu, Hua; Nomura, Saeko et al. (2002) Abnormal B lymphocyte development and autoimmunity in hypoxia-inducible factor 1alpha -deficient chimeric mice. Proc Natl Acad Sci U S A 99:2170-4
Armstrong, J M; Chen, J F; Schwarzschild, M A et al. (2001) Gene dose effect reveals no Gs-coupled A2A adenosine receptor reserve in murine T-lymphocytes: studies of cells from A2A-receptor-gene-deficient mice. Biochem J 354:123-30
Lukashev, D; Caldwell, C; Ohta, A et al. (2001) Differential regulation of two alternatively spliced isoforms of hypoxia-inducible factor-1 alpha in activated T lymphocytes. J Biol Chem 276:48754-63
Ohta, A; Sitkovsky, M (2001) Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414:916-20

Showing the most recent 10 out of 13 publications