Published Online
on April 24, 2006

A more recent version of this article appeared on May 2, 2006

This Article Full Text (PDF) All Versions of this Article: 113/17/2105    most recent CIRCULATIONAHA.105.593046v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yilmaz, G. Articles by Granger, D. N. Search for Related Content PubMed PubMed Citation Articles by Yilmaz, G. Articles by Granger, D. N. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Medline Plus Health Information Stroke Related Collections Genetically altered mice Growth factors/cytokines Ischemic biology - basic studies Acute Cerebral Infarction Risk Factors for Stroke

Submitted on October 4, 2005
Revised on January 11, 2006
Accepted on March 1, 2006

Role of T Lymphocytes and Interferon- in Ischemic Stroke

Gokhan Yilmaz MD, Thiruma V. Arumugam PhD, Karen Y. Stokes PhD, and D. Neil Granger PhD^*

From the Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport.

^* To whom correspondence should be addressed. E-mail: dgrang{at}lsuhsc.edu.

Background--Although lymphocyte recruitment and activation are associated with cerebral ischemia-reperfusion (I/R) injury, the contributions of specific lymphocyte subpopulations and lymphocyte-derived interferon- (IFN-) to stroke remain unknown. The objectives of this study were to define the contribution of specific populations of lymphocytes to the inflammatory and prothrombogenic responses elicited in the cerebral microvasculature by I/R and to investigate the role of T-cell-associated IFN- in the pathogenesis of ischemic stroke.

Methods and Results--Middle cerebral artery occlusion was induced for 1 hour (followed by 4 or 24 hours of reperfusion) in wild-type mice and mice deficient in lymphocytes (Rag1^-/-), CD4⁺ T cells, CD8⁺ T cells, B cells, or IFN-. Platelet and leukocyte adhesion was assessed in cortical venules with intravital video microscopy. Neurological deficit and infarct volume were determined 24 hours after reperfusion. Rag1^-/-, CD4⁺ T-cell^-/-, CD8⁺ T-cell^-/-, and IFN-^-/- mice exhibited comparable significant reductions in I/R-induced leukocyte and platelet adhesion compared with wild-type mice exposed to I/R. Infarct volume was reduced and I/R-induced neurological deficit was improved in immunodeficient Rag1^-/- mice. These protective responses were reversed in Rag1^-/- mice reconstituted with either wild-type or, to a lesser extent, IFN-^-/- splenocytes. B-cell-deficient mice failed to show improvement against ischemic stroke injury.

Conclusions--These findings indicate that CD4⁺ and CD8⁺ T lymphocytes, but not B lymphocytes, contribute to the inflammatory and thrombogenic responses, brain injury, and neurological deficit associated with experimental stroke. Although IFN- plays a pivotal role in stroke-induced inflammatory responses, T lymphocytes appear to be a minor source of this cytokine.

Key words: cerebral ischemia • leukocytes • lymphocytes • microcirculation • platelets

This article has been cited by other articles:

				S. R. Satpute, J. M. Park, H. R. Jang, P. Agreda, M. Liu, M. T. Gandolfo, L. Racusen, and H. Rabb The Role for T Cell Repertoire/Antigen-Specific Interactions in Experimental Kidney Ischemia Reperfusion Injury J. Immunol., July 15, 2009; 183(2): 984 - 992. [Abstract] [Full Text] [PDF]

				S. Subramanian, B. Zhang, Y. Kosaka, G. G. Burrows, M. R. Grafe, A. A. Vandenbark, P. D. Hurn, and H. Offner Recombinant T Cell Receptor Ligand Treats Experimental Stroke Stroke, July 1, 2009; 40(7): 2539 - 2545. [Abstract] [Full Text] [PDF]

				M. Gelderblom, F. Leypoldt, K. Steinbach, D. Behrens, C.-U. Choe, D. A. Siler, T. V. Arumugam, E. Orthey, C. Gerloff, E. Tolosa, et al. Temporal and Spatial Dynamics of Cerebral Immune Cell Accumulation in Stroke Stroke, May 1, 2009; 40(5): 1849 - 1857. [Abstract] [Full Text] [PDF]

				M. Osman, J. Russell, and D. N. Granger Lymphocyte-derived interferon-{gamma} mediates ischemia-reperfusion-induced leukocyte and platelet adhesion in intestinal microcirculation Am J Physiol Gastrointest Liver Physiol, March 1, 2009; 296(3): G659 - G663. [Abstract] [Full Text] [PDF]

				L. Wang, O. Zis, G. Ma, Z. Shan, X. Zhang, S. Wang, C. Dai, J. Zhao, Q. Lin, S. Lin, et al. Upregulation of Macrophage Migration Inhibitory Factor Gene Expression in Stroke Stroke, March 1, 2009; 40(3): 973 - 976. [Abstract] [Full Text] [PDF]

				M. Austinat, S. Braeuninger, J. B. Pesquero, M. Brede, M. Bader, G. Stoll, T. Renne, and C. Kleinschnitz Blockade of Bradykinin Receptor B1 but Not Bradykinin Receptor B2 Provides Protection From Cerebral Infarction and Brain Edema * Expanded Materials and Methods Stroke, January 1, 2009; 40(1): 285 - 293. [Abstract] [Full Text] [PDF]

				D. B. Ascon, M. Ascon, S. Satpute, S. Lopez-Briones, L. Racusen, R. B. Colvin, M. J. Soloski, and H. Rabb Normal mouse kidneys contain activated and CD3+CD4-CD8- double-negative T lymphocytes with a distinct TCR repertoire J. Leukoc. Biol., December 1, 2008; 84(6): 1400 - 1409. [Abstract] [Full Text] [PDF]

				S. Schwarting, S. Litwak, W. Hao, M. Bahr, J. Weise, and H. Neumann Hematopoietic Stem Cells Reduce Postischemic Inflammation and Ameliorate Ischemic Brain Injury Stroke, October 1, 2008; 39(10): 2867 - 2875. [Abstract] [Full Text] [PDF]

				S. Terao, G. Yilmaz, K. Y. Stokes, J. Russell, M. Ishikawa, T. Kawase, and D. N. Granger Blood Cell-Derived RANTES Mediates Cerebral Microvascular Dysfunction, Inflammation, and Tissue Injury After Focal Ischemia-Reperfusion Stroke, September 1, 2008; 39(9): 2560 - 2570. [Abstract] [Full Text] [PDF]

				S. Terao, G. Yilmaz, K. Y. Stokes, M. Ishikawa, T. Kawase, and D. N. Granger Inflammatory and Injury Responses to Ischemic Stroke in Obese Mice Stroke, March 1, 2008; 39(3): 943 - 950. [Abstract] [Full Text] [PDF]

				T. P. Obrenovitch Molecular Physiology of Preconditioning-Induced Brain Tolerance to Ischemia Physiol Rev, January 1, 2008; 88(1): 211 - 247. [Abstract] [Full Text] [PDF]

				M. Ishikawa, E. Sekizuka, N. Yamaguchi, H. Nakadate, S. Terao, D. N. Granger, and H. Minamitani Angiotensin II type 1 receptor signaling contributes to platelet-leukocyte-endothelial cell interactions in the cerebral microvasculature Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2306 - H2315. [Abstract] [Full Text] [PDF]

				A. E. Baird Blood Genomics in Human Stroke Stroke, February 1, 2007; 38(2): 694 - 698. [Abstract] [Full Text] [PDF]

				U. Dirnagl, J. Klehmet, J. S. Braun, H. Harms, C. Meisel, T. Ziemssen, K. Prass, and A. Meisel Stroke-Induced Immunodepression: Experimental Evidence and Clinical Relevance Stroke, February 1, 2007; 38(2): 770 - 773. [Abstract] [Full Text] [PDF]

				J. M. Gee, A. Kalil, C. Shea, and K. J. Becker Lymphocytes: Potential Mediators of Postischemic Injury and Neuroprotection Stroke, February 1, 2007; 38(2): 783 - 788. [Abstract] [Full Text] [PDF]

				A. E. Baird The Forgotten Lymphocyte: Immunity and Stroke Circulation, May 2, 2006; 113(17): 2035 - 2036. [Full Text] [PDF]