Lack of intrinsic CTLA-4 expression has minimal effect on regulation of antiviral T-cell immunity.
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.
Homann
Dirk
D
Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center. Mail stop B140, P.O. Box 6511, Aurora, CO 80045, USA. dirk.homann@uchsc.edu
Dummer
Wolfgang
W
Wolfe
Tom
T
Rodrigo
Evelyn
E
Theofilopoulos
Argyrios N
AN
Oldstone
Michael B A
MB
von Herrath
Matthias G
MG
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D060908:CTLA-4 Antigen; D005786:Gene Expression Regulation / Q000276:immunology; D020868:Gene Silencing; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000821:virology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse