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Altered Composition of the Immunological Synapse in an Anergic, Age-Dependent Memory T Cell Subset¹

Michael D. Eisenbraun^*,, Ami Tamir and Richard A. Miller^2,*,,,§

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

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- 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.

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