Abstract
Positive selection of developing thymocytes is initiated at the double-positive (DP) CD4(+)CD8(+) stage of their maturation. Accordingly, expression of a human CD4 (hCD4) transgene beginning at the DP stage has been shown to restore normal T cell development and function in CD4-deficient mice. However, it is unclear whether later onset CD4 expression would still allow such a restoration. To investigate this issue, we used transgenic mice in which a hCD4 transgene is not expressed on DP, but only on single-positive cells. By crossing these animals with CD4-deficient mice, we show that late hCD4 expression supports the maturation of T cell precursors and the peripheral export of mature TCRalphabeta(+) CD8(-) T cells. These results were confirmed in two different MHC class II-restricted TCR transgenic mice. T cells arising by this process were functional in the periphery because they responded to agonist peptide in vivo. Interestingly, thymocytes of these mice appeared refractory to peptide-induced negative selection. Together, these results indicate that the effect of CD4 on positive selection of class II-restricted T cells extends surprisingly late into the maturation process by a previously unrecognized pathway of differentiation, which might contribute to the generation of autoreactive T cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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CD4 Antigens / biosynthesis*
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CD4 Antigens / genetics*
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CD4 Antigens / metabolism
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CD8-Positive T-Lymphocytes / cytology
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Movement / genetics
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Cell Movement / immunology*
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Clonal Deletion / genetics
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Crosses, Genetic
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Cytochrome c Group / administration & dosage
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Cytochrome c Group / immunology
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Gene Expression Regulation / immunology
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Histocompatibility Antigens Class II / genetics
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Humans
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Injections, Intravenous
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Lymphocyte Activation / genetics
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Mice
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Mice, Knockout
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Mice, Transgenic
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Molecular Sequence Data
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Organ Specificity / genetics
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Organ Specificity / immunology
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Peptides / administration & dosage
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Peptides / immunology
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Receptors, Antigen, T-Cell, alpha-beta / biosynthesis
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Stem Cells / cytology
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Stem Cells / immunology
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Stem Cells / metabolism
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T-Lymphocyte Subsets / cytology*
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism
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Thymus Gland / cytology*
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Thymus Gland / immunology*
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Thymus Gland / metabolism
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Time Factors
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Transgenes / immunology*
Substances
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CD4 Antigens
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Cytochrome c Group
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Histocompatibility Antigens Class II
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Peptides
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Receptors, Antigen, T-Cell, alpha-beta