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,§,
,§,¶
*
Department of Pathology,
Cellular and Molecular Biology Graduate Program, and
Geriatrics Center, University of Michigan School of Medicine, Ann Arbor, MI 48109;
§
University of Michigan Institute of Gerontology, Ann Arbor, MI 48109; and
¶
Ann Arbor Department of Veterans Affairs Medical Center, Ann Arbor, MI 48109
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-
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.
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