Affiliation:
1. Division of Virology, Department of Neuropharmacology
2. Department of Immunology, The Scripps Research Institute
3. Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, California
Abstract
ABSTRACT
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.
Publisher
American Society for Microbiology
Subject
Virology,Insect Science,Immunology,Microbiology
Reference92 articles.
1. Alegre, M.-L., K. A. Frauwirth, and C. B. Thompson. 2001. T cell regulation by CD28 and CTLA-4. Nat. Rev. Immunol.1:220-228.
2. Allison, J. P., and M. F. Krummel. 1995. The Yin and Yang of T cell costimulation. Science270:932-933.
3. Bachmann, M. F., A. Gallimore, E. Jones, B. Ecabert, H. Acha-Orbea, and M. Kopf. 2001. Normal pathogen-specific immune responses mounted by CTLA-4-deficient T cells: a paradigm reconsidered. Eur. J. Immunol.31:450-458.
4. Bachmann, M. F., G. Kohler, B. Ecabert, T. W. Mak, and M. Kopf. 1999. Cutting edge: lymphoproliferative disease in the absence of CTLA-4 is not T cell autonomous. J. Immunol.163:1128-1131.
5. Bachmann, M. F., P. Waterhouse, D. E. Speiser, K. McKall-Faienza, T. W. Mak, and P. S. Ohashi. 1998. Normal responsiveness of CTLA-4-deficient anti-viral cytotoxic T cells. J. Immunol.160:95-100.
Cited by
50 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献