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Published online before print March 18, 2008
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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070892

Accepted for publication December 12, 2007.

Article

Antigen-Induced Pten Gene Deletion in T Cells Exacerbates Neuropathology in Experimental Autoimmune Encephalomyelitis

Trina A. Johnson, Shigeki Tsutsui, and Frank R. Jirik@

From the Department of Biochemistry and Molecular Biology, McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Canada

@ To whom correspondence should be addressed. E-mail: jirik{at}ucalgary.ca.


  Abstract

The Pten tumor suppressor gene is critical for normal intrathymic development of T cells; however, its role in mature antigen-activated T cells is less well defined. A genetically crossed mouse line, Ptenfl/fl GBC, in which Pten gene deletions could be primarily confined to antigen-activated CD8+ T cells, enabled us to evaluate the consequences of Pten loss on the course of experimental autoimmune encephalomyelitis. Compared with Ptenfl/fl controls, myelin oligodendrocyte glycoprotein (MOG) peptide-immunized Ptenfl/fl GBC mice developed more severe and protracted disease. This was accompanied by increased spinal cord white matter myelin basic protein depletion and axonal damage, as well as a striking persistence of macrophage and granzyme B-expressing cellular neuroinfiltrates in the chronic phase of the disease. This persistence may be explained by the observation that anti-CD3 activated Ptenfl/fl GBC T cells were more resistant to proapoptotic stimuli. Consistent with the predicted consequences of Pten loss, purified CD8+ T cells from Ptenfl/fl GBC mice displayed augmented proliferative responses to anti-T-cell receptor stimulation, and MOG-primed Ptenfl/fl GBC T cells exhibited a reduced activation threshold to MOG peptide. Ptenfl/fl GBC mice also developed atypical central nervous system disease, manifested by prominent cervical cord and forebrain involvement. Collectively, our findings indicate that the phosphatidylinositol 3-kinase signaling pathway is an essential regulator of CD8+ T-cell effector function in experimental autoimmune encephalomyelitis.






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Copyright © 2008 by the American Society for Investigative Pathology.