Age-dependent defects in TCR-triggered cytoskeletal rearrangement in CD4+ T cells.
Previous research has shown that many of the CD4 T cells from older mice do not form functional immune synapses after conjugation with peptide-pulsed APC. We now show that the defect lies at a very early stage in the cytoskeletal reorganization that precedes movement of protein kinases and their substrates to the TCR/APC interface. Antagonist peptides presented to T cells from young mice induce migration of talin (but not paxillin, vinculin, or F-actin) to the APC contact zone, but CD4 T cells from older donors typically fail to show the talin polarization response. A spreading assay in which contact with anti-CD3-coated slides induces CD4 T cells to assume a conical shape and develop lammelopodia also shows a decline with age in the proportion of T cells that can initiate cytoskeletal changes in response to this simplified stimulus. Finally, the transition from detergent-soluble to cytoskeletal forms of the p16, p21, and p23 isoforms of CD3zeta in response to CD3/CD4/CD28 cross-linking is much stronger in young than in old T cells. Thus, defects in cytoskeletal reorganization triggered by initial contact between TCR and peptide-bearing APC precede, and presumably contribute to, defective activation of protein kinase-mediated signals in the first few minutes of the activation cascade in T cells from aged mice.
Garcia
Gonzalo G
GG
Department of Pathology, School of Medicine, and Institute of Gerontology, University of Michigan, Ann Arbor 48109, USA.
Miller
Richard A
RA
D048868:Adaptor Proteins, Signal Transducing; D000375:Aging / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D001710:Biotin / Q000235:genetics; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D003599:Cytoskeleton / Q000276:immunology* / Q000378:metabolism*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D051380:GRB2 Adaptor Protein; D005982:Glutathione Transferase / Q000235:genetics; D007399:Interphase / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010455:Peptides / Q000276:immunology; D021381:Protein Transport / Q000276:immunology; D011506:Proteins / Q000235:genetics; D011554:Pseudopodia / Q000276:immunology / Q000378:metabolism; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D018984:Epitopes, T-Lymphocyte; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D010455:Peptides; D011506:Proteins; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D001710:Biotin; D005982:Glutathione Transferase