Abstract
CTLA-4 inhibits T-cell activation and protects against the development of autoimmunity. We and others previously showed that the coreceptor can induce T-cell motility and shorten dwell times with dendritic cells (DCs). However, it has been unclear whether this property of CTLA-4 affects both conventional T cells (Tconvs) and regulatory T cells (Tregs). Here, we report that CTLA-4 had significantly more potent effects on the motility and contact times of Tconvs than Tregs. This was shown firstly by anti-CTLA-4 reversal of the anti-CD3 stop-signal on FoxP3-negative cells at concentrations that had no effect on FoxP3-positive Tregs. Secondly, the presence of CTLA-4 reduced the contact times of DO11.10 x CD4(+)CD25(-) Tconvs, but not DO11.10 x CD4(+)CD25(+) Tregs, with OVA peptide presenting DCs in lymph nodes. Thirdly, blocking of CTLA-4 with anti-CTLA-4 Fab increased the contact times of Tconvs, but not Tregs with DCs. By contrast, the presence of CD28 in a comparison of Cd28(-/-) and Cd28(+/+) DO11.10 T cells had no detectable effect on the contact times of either Tconvs or Tregs with DCs. Our findings identify for the first time a mechanistic explanation to account for CTLA-4-negative regulation of Tconv cells but not Tregs in immune responses.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies / immunology
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Antibodies / pharmacology
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CD28 Antigens / immunology
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CD28 Antigens / metabolism
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CTLA-4 Antigen / genetics
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CTLA-4 Antigen / immunology*
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CTLA-4 Antigen / metabolism
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Cell Migration Assays
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Cell Movement / drug effects
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Cell Movement / immunology
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Cells, Cultured
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Forkhead Transcription Factors / immunology
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Forkhead Transcription Factors / metabolism
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Lymph Nodes / cytology
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Lymph Nodes / immunology
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Lymph Nodes / metabolism
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Mice
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Mice, Knockout
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Mice, Transgenic
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Ovalbumin / immunology
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Ovalbumin / pharmacology
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / immunology*
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Receptors, Antigen, T-Cell / metabolism
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Signal Transduction / drug effects
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Signal Transduction / immunology*
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism
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Time Factors
Substances
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Antibodies
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CD28 Antigens
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CTLA-4 Antigen
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Ctla4 protein, mouse
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Receptors, Antigen, T-Cell
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Green Fluorescent Proteins
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Ovalbumin