Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells.
CTLA-4-deficient animals develop a fatal lymphoproliferative disorder. The cellular mechanism(s) responsible for this phenotype have not been determined. Here, we show that there is a preferential expansion of CD4+ T cells in CTLA-4(-/-) mice, which results in a skewing of the CD4/CD8 T cell ratio. In vivo antibody depletion of CD8+ T cells from birth does not alter the onset or the severity of the CD28-dependent lymphoproliferative disorder. In contrast, CD4+ T cell depletion completely prevents all features characteristic of the lymphoproliferation observed in CTLA-4-deficient mice. These results demonstrate that CD4+ T cells initiate the phenotype in the CTLA-4(-/-) mice. Further, these results suggest that the role of CTLA-4 in peripheral CD4+ versus CD8+ T cell homeostasis is distinct.
Chambers
C A
CA
Howard Hughes Medical Institute, Department of Molecular and Cellular Biology, University of California, Berkeley 94720, USA.
Sullivan
T J
TJ
Allison
J P
JP
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D060908:CTLA-4 Antigen; D002453:Cell Cycle; D002455:Cell Division; D017353:Gene Deletion; D018796:Immunoconjugates; D008212:Lymphocyte Depletion; D008221:Lymphoid Tissue; D008232:Lymphoproliferative Disorders / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010641:Phenotype
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D000069594:Abatacept