Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4

The B7-CD28/CTLA-4 costimulatory pathway can provide a signal pivotal for T cell activation. Signaling through this pathway is complex due to the presence of two 137 family members, B7-1 and B7-2, and two counterreceptors, CD28 and CTLA-4. Studies with anti-CTLA-4 monoclonal antibodies have suggeste...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Mass.), 1995-11, Vol.3 (5), p.541-547
Main Authors: Tivol, Elizabeth A., Borriello, Frank, Schweitzer, A.Nicola, Lynch, William P., Bluestone, Jeffrey A., Sharpe, Arlene H.
Format: Article
Language:English
Subjects:
Abatacept
Animals
Antigens, CD
Antigens, Differentiation - genetics
Antigens, Differentiation - immunology
Antigens, Differentiation - physiology
Base Sequence
Cells, Cultured
CTLA-4 Antigen
Cytokines - biosynthesis
DNA Primers - chemistry
Down-Regulation - genetics
Immunoconjugates
Immunohistochemistry
Lymphocyte Activation - genetics
Lymphoid Tissue - pathology
Lymphoproliferative Disorders - genetics
Lymphoproliferative Disorders - mortality
Lymphoproliferative Disorders - pathology
Mice
Mice, Mutant Strains
Mice, Transgenic
Molecular Sequence Data
T-Lymphocytes - immunology
T-Lymphocytes - metabolism
Viscera - pathology
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Summary:The B7-CD28/CTLA-4 costimulatory pathway can provide a signal pivotal for T cell activation. Signaling through this pathway is complex due to the presence of two 137 family members, B7-1 and B7-2, and two counterreceptors, CD28 and CTLA-4. Studies with anti-CTLA-4 monoclonal antibodies have suggested both positive and negative roles for CTLA-4 in T cell activation. To elucidate the in vivo function of CTLA-4, we generated CTLA-4-deficient mice. These mice rapidly develop lymphoproliferative disease with multiorgan lymphocytic infiltration and tissue destruction, with particularly severe myocarditis and pancreatitis, and die by 3–4 weeks of age. The phenotype of the CTLA-4-deficient mouse strain is supported by studies that have suggested a negative role for CTLA-4 in T cell activation. The severe phenotype of mice lacking CTLA-4 implies a critical role for CTLA-4 in down-regulating T cell activation and maintaining immunologic hemeostasis. In the absence of CTLA-4, peripheral T cells are activated, can spontaneously proliferate, and may mediate lethal tissue injury.
ISSN:1074-7613
1097-4180
DOI:10.1016/1074-7613(95)90125-6