Abstract
In young mice, memory CD4 T lymphocytes with high P-glycoprotein activity (P-gp(high)) are unresponsive to TCR stimulation in vitro but can be activated by PMA plus ionomycin. The proportion of these hyporesponsive cells increases considerably with age. The earliest events in T cell activation were studied in P-gp(high) and P-gp(low) CD4 memory cells at the single-cell level using confocal immunofluorescence methods. Recruitment of both linker for activation of T cells (LAT) and protein kinase C-theta to the immunological synapse, i.e., the site of T cell interaction with stimulator cells, was greatly impaired in P-gp(high) cells from both young and old mice. Translocation of NF-AT to the nucleus, CD69 expression, and proliferative capacity were also diminished to a similar extent in P-gp(high) cells under the same activation conditions. In contrast, movement of c-Cbl to the synapse region occurred in a high proportion of CD4 memory T cells regardless of P-gp subset or age. Moreover, although P-gp(low) cells frequently recruited both c-Cbl and LAT to the APC synapse, cells in the less responsive P-gp(high) subset frequently relocated c-Cbl, but not LAT, to the interface region. In some systems, c-Cbl can act as a negative regulator of receptor-dependent tyrosine kinases, and alterations of c-Cbl to LAT ratios in the P-gp(high) subset may thus contribute to the hyporesponsiveness of this age-dependent, anergic memory cell population.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
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Adaptor Proteins, Signal Transducing*
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Aging / immunology*
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Animals
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Antigens, CD / biosynthesis
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Antigens, Differentiation, T-Lymphocyte / biosynthesis
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Biological Transport / immunology
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CD4-Positive T-Lymphocytes / enzymology
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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Carrier Proteins / metabolism
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Cell Line
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Cell Nucleus / metabolism
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Clonal Anergy*
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DNA-Binding Proteins / metabolism
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Immunologic Memory*
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Isoenzymes / metabolism
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Lectins, C-Type
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Male
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Membrane Proteins*
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Mice
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Mice, Inbred C57BL
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Mice, Inbred CBA
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Models, Immunological
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NFATC Transcription Factors
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Nuclear Proteins*
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Phosphoproteins / metabolism
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Protein Kinase C / metabolism
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Protein Kinase C-theta
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-cbl
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T-Lymphocyte Subsets / enzymology
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism*
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Transcription Factors / metabolism
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Ubiquitin-Protein Ligases*
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Adaptor Proteins, Signal Transducing
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Antigens, CD
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Antigens, Differentiation, T-Lymphocyte
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CD69 antigen
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Carrier Proteins
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DNA-Binding Proteins
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Isoenzymes
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Lat protein, mouse
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Lectins, C-Type
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Membrane Proteins
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NFATC Transcription Factors
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Nuclear Proteins
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Phosphoproteins
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Proto-Oncogene Proteins
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Transcription Factors
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Proto-Oncogene Proteins c-cbl
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Ubiquitin-Protein Ligases
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Prkcq protein, mouse
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Protein Kinase C
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Protein Kinase C-theta
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Cbl protein, mouse