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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

Dirk Homann,^1*, Wolfgang Dummer,^2, 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.

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

D.H. and W.D. contributed equally to this work.

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