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Journal of Virology, January 2006, p. 270-280, Vol. 80, No. 1
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.1.270-280.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Lack of Intrinsic CTLA-4 Expression Has Minimal Effect on Regulation of Antiviral T-Cell Immunity{dagger}

Dirk Homann,1*,{ddagger} Wolfgang Dummer,2,{ddagger} Tom Wolfe,3 Evelyn Rodrigo,3 Argyrios N. Theofilopoulos,2 Michael B. A. Oldstone,1 and Matthias G. von Herrath3

Division of Virology, Department of Neuropharmacology,1 Department of Immunology, The Scripps Research Institute,2 Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, California3

Received 13 June 2005/ Accepted 6 October 2005

CTLA-4 is considered one of the most potent negative regulators of T-cell activation. To circumvent experimental limitations due to fatal lymphoproliferative disease associated with genetic ablation of CTLA-4, we have used radiation chimeras reconstituted with a mixture of CTLA-4+/+ and CTLA-4–/– bone marrow that retain a normal phenotype and allow the evaluation of long-term T-cell immunity under conditions of intrinsic CTLA-4 deficiency. Following virus infection, we profiled primary, memory, and secondary CD8+ and CD4+ T-cell responses directed against eight different viral epitopes. Our data demonstrate unaltered antigen-driven proliferation, acquisition of effector functions, distribution of epitope hierarchies, T-cell receptor repertoire selection, functional avidities, and long-term memory maintenance in the absence of CTLA-4. Moreover, regulation of memory T-cell survival and homeostatic proliferation, as well as secondary responses, was equivalent in virus-specific CTLA4+/+ and CTL-A-4–/– T-cell populations. Thus, lack of CTLA-4 expression by antigen-specific T cells can be compensated for by extrinsic factors in the presence of CTLA-4 expression by other cells. These findings have implications for the physiologic, pathological, and therapeutic regulation of costimulation.

* Corresponding author. Present address for Dirk Homann: Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center. Mail stop B140, P.O. Box 6511, Aurora, CO 80045. Phone: (303) 724-6843. Fax: (303) 724-6830. E-mail: dirk.homann{at}uchsc.edu. Mailing address for Matthias G. von Herrath: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive (IMM6), San Diego, CA 92121. Phone: (858) 558-3571. Fax: (858) 558-3579. E-mail: matthias{at}liai.org.

{dagger} Report 15037-NP from The Scripps Research Institute and 488 from the La Jolla Institute for Allergy and Immunology.

{ddagger} D.H. and W.D. contributed equally to this work.

Journal of Virology, January 2006, p. 270-280, Vol. 80, No. 1
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.1.270-280.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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