CD73 is required for efficient entry of lymphocytes into the central nervous system during experimental autoimmune encephalomyelitis.
CD73 is a cell surface enzyme of the purine catabolic pathway that catalyzes the breakdown of AMP to adenosine. Because of the strong immunosuppressive and antiinflammatory properties of adenosine, we predicted that cd73(-/-) mice would develop severe experimental autoimmune encephalomyelitis (EAE), an animal model for the central nervous system (CNS) inflammatory disease, multiple sclerosis. Surprisingly, cd73(-/-) mice were resistant to EAE. However, CD4 T cells from cd73(-/-) mice secreted more proinflammatory cytokines than wild-type (WT) mice and were able to induce EAE when transferred into naïve cd73(+/+) T cell-deficient recipients. Therefore, the protection from EAE observed in cd73(-/-) mice was not caused by a deficiency in T cell responsiveness. Immunohistochemistry showed that cd73(-/-) mice had fewer infiltrating lymphocytes in their CNS compared with WT mice. Importantly, susceptibility to EAE could be induced in cd73(-/-) mice after the transfer of WT CD73(+)CD4(+) T cells, suggesting that CD73 must be expressed either on T cells or in the CNS for disease induction. In the search for the source of CD73 in the CNS that might facilitate lymphocyte migration, immunohistochemistry revealed a lack of CD73 expression on brain endothelial cells and high expression in the choroid plexus epithelium which regulates lymphocyte immunosurveillance between the blood and cerebrospinal fluid. Because blockade of adenosine receptor signaling with the A(2a) adenosine receptor-specific antagonist SCH58261 protected WT mice from EAE induction, we conclude that CD73 expression and adenosine receptor signaling are required for the efficient entry of lymphocytes into the CNS during EAE development.
Mills
Jeffrey H
JH
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
Thompson
Linda F
LF
Mueller
Cynthia
C
Waickman
Adam T
AT
Jalkanen
Sirpa
S
Niemela
Jussi
J
Airas
Laura
L
Bynoe
Margaret S
MS
D015720:5'-Nucleotidase / Q000276:immunology*; D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology*; D002490:Central Nervous System / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D004198:Disease Susceptibility; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology* / Q000276:immunology*; D007114:Immunization; D020381:Interleukin-17 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D051379:Mice; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D058915:Purinergic P1 Receptor Antagonists; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology
D020381:Interleukin-17; D053583:Interleukin-1beta; D018992:Myelin-Associated Glycoprotein; D058915:Purinergic P1 Receptor Antagonists; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015720:5'-Nucleotidase