Abstract
Engagement of CTLA-4 is critical for inhibiting T cell immune responses. Recent studies have shown that CTLA-4 plays a key role in regulating peripheral T cell tolerance. It has been suggested that one mechanism by which CTLA-4 performs this function is by regulating cell cycle progression. Here, we investigate in depth the role of CTLA-4 in regulating cell cycle progression in naive T cells by comparing the immune responses in the absence or presence of CTLA-4. In the absence of CLTA-4, T cells exhibit marked increases in T cell proliferation, IL-2 mRNA and protein secretion, and cells cycling in the S and G2-M phase. Analyses of cyclins, cyclin-dependent kinases, and cell cycle inhibitors involved in the transition from the G1 to S phase reveal that cell cycle progression is prolonged in the absence of CTLA-4. This is due to the early exit from the G1 phase, entry into the S phase, and prolonged S phase period. Re-expression of the cell cycle inhibitor p27(kip1) is delayed in the absence of CTLA-4. These studies demonstrate that the B7 : CTLA-4 pathway exerts its major effects on T cell immune responses via regulation of the cell cycle.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Abatacept
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Animals
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Antigens, CD / genetics
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Antigens, CD / physiology
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Antigens, Differentiation / genetics
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Antigens, Differentiation / physiology*
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B7-1 Antigen / genetics
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B7-1 Antigen / physiology
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B7-2 Antigen
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CTLA-4 Antigen
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Cell Cycle / immunology*
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Cell Cycle Proteins / metabolism
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclin-Dependent Kinases / biosynthesis
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Cyclins / biosynthesis
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Female
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G1 Phase / immunology
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Immunoconjugates*
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In Vitro Techniques
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Interleukin-2 / biosynthesis
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Lymphocyte Activation
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology
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Mice
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Mice, Knockout
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S Phase / immunology
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T-Lymphocytes / cytology*
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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Tumor Suppressor Proteins / metabolism
Substances
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Antigens, CD
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Antigens, Differentiation
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B7-1 Antigen
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B7-2 Antigen
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CTLA-4 Antigen
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Cd86 protein, mouse
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Cdkn1b protein, mouse
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Cell Cycle Proteins
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Ctla4 protein, mouse
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Cyclins
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Immunoconjugates
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Interleukin-2
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Membrane Glycoproteins
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27
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Abatacept
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Cyclin-Dependent Kinases