Age-dependent alterations in the assembly of signal transduction complexes at the site of T cell/APC interaction.
TCR interaction with peptide-MHC complexes triggers migration of protein kinases, actin-binding proteins, and other accessory molecules to the T cell/APC synapse. We used confocal immunofluorescence methods to show that the adapter protein LAT (linker for activation of T cells) and the guanine nucleotide exchange factor Vav also move to the APC interface in mouse CD4 T cells conjugated to anti-CD3 hybridoma cells, and in TCR-transgenic CD4 cells conjugated to APC bearing agonist (but not closely related nonagonist) peptides. The proportion of CD4+ T cells able to relocalize LAT or Vav, or to relocate cytoplasmic NT-AT (NF-ATc) from cytoplasm to nucleus, declines about 2-fold in aged mice. The decline in LAT relocalization is accompanied by a similar decline in tyrosine phosphorylation of LAT in CD4 cells stimulated by CD3/CD4 cross-linking. Two-color experiments show that LAT redistribution is strongly associated with relocalization of both NF-ATc and protein kinase C-theta among individual cells. LAT migration to the immunological synapse depends on actin polymerization as well as on activity of Src family kinases, but aging leads to only a small change in the percentage of CD4 cells that redistribute F-actin to the site of APC contact. These results suggest that defects in the ability of T cells from aged donors to move kinase substrates and coupling factors, including LAT and Vav, into the T cell/APC contact region may contribute to the decline with age in NF-ATc-dependent gene expression, and thus to defects in T cell clonal expansion.
Tamir
A
A
Department of Pathology, Cellular and Molecular Biology Graduate Program, and Geriatrics Center, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
Eisenbraun
M D
MD
Garcia
G G
GG
Miller
R A
RA
D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000375:Aging / Q000276:immunology*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D001692:Biological Transport / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology*; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism; D002499:Centrifugation, Density Gradient; D004268:DNA-Binding Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D000074121:Protein Kinase C-theta; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav; D015398:Signal Transduction / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D007527:Isoenzymes; C491734:Lat protein, mouse; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D014157:Transcription Factors; C496619:Vav1 protein, mouse; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta