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Dynamic Imaging of T Cell-Parasite Interactions in the Brains of Mice Chronically Infected with Toxoplasma gondii¹

Marie Schaeffer^*, Seong-Ji Han^*, Tatyana Chtanova^*, Giel G. van Dooren, Paul Herzmark^*, Ying Chen, Badrinath Roysam, Boris Striepen^2, and Ellen A. Robey^2,*

^* Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720; Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, GA 30602; and Department of Electrical, Computer, and System Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180

The intracellular parasite Toxoplasma gondii can establish persistent infection in the brain of a mammalian host, a standoff that involves the active participation of host CD8 T cells to control infection. CD8 T cells generally protect against intracellular pathogens by local delivery of effector molecules upon recognition of specific pathogen Ags on invaded host cells. However, the interactions between CD8 T cells, T. gondii, and APCs in the brain have not yet been examined. In this study we have used a mouse infection model in conjunction with two-photon microscopy of living brain tissue and confocal microscopy of fixed brain sections to examine the interactions between CD8 T cells, parasites, and APCs from chronically infected mice. We found that Ag-specific CD8 T cells were recruited to the brains of infected mice and persisted there in the presence of ongoing Ag recognition. Cerebral CD8 T cells made transient contacts with granuloma-like structures containing parasites and with individual CD11b⁺ APCs, including some that did not contain parasites. In contrast, T cells ignored intact Ag-bearing cysts and did not contact astrocytes or neurons, including neurons containing parasites or cysts. Our data represent the first direct observation of the dynamics of T cell-parasite interactions within living tissue and provide a new perspective for understanding immune responses to persistent pathogens in the brain.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was funded by the National Institutes of Health (to B.S. and E.R.), Human Frontier Science Program Fellowship (to T.C.), and C. J. Martin Overseas Fellowship 400489 from the Australian National Health and Medical Research Council (to G.v.D.).

² Address correspondence and reprint requests to Dr. Ellen A. Robey, Department of Molecular and Cell Biology, 471 Life Sciences Addition, University of California, Berkeley, CA 94720. E-mail address: erobey{at}berkeley.edu or Dr. Boris Striepen, Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Paul D. Coverdell Center, 500 D. W. Brooks Drive, Athens, GA 30602. E-mail address: striepen{at}cb.uga.edu

³ Abbreviations used in this paper: CFP, cyan fluorescent protein; GFAP, glial fibrillary acid protein; MAP, microtubule-associated protein; RFP, red fluorescent protein; YFP, yellow fluorescent protein.

⁴ The online version of this article contains supplemental material.