Altered composition of the immunological synapse in an anergic, age-dependent memory T cell subset.
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.
Eisenbraun
M D
MD
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
Tamir
A
A
Miller
R A
RA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D048868:Adaptor Proteins, Signal Transducing; D000375:Aging / Q000276:immunology*; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D001692:Biological Transport / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D017635:Clonal Anergy; D004268:DNA-Binding Proteins / Q000378:metabolism; D007156:Immunologic Memory; D007527:Isoenzymes / Q000378:metabolism; D037181:Lectins, C-Type; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018448:Models, Immunological; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D000074121:Protein Kinase C-theta; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D000099192:CD69 Antigens
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D037181:Lectins, C-Type; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D000099192:CD69 Antigens; C491734:Lat protein, mouse; C489593:Prkcq protein, mouse; C493849:Cbl protein, mouse