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 activat ed by PMA plus ionomycin, The proportion of these hyporesponsive cells incr eases 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 lev el using confocal immunofluorescence methods. Recruitment of both linker fo r activation of T cells (LAT) and protein kinase C-theta to the immunologic al 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. Translo cation 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 sam e activation conditions. In contrast, movement of c-Cbl to the synapse regi on occurred in a high proportion of CD4 memory T cells regardless of P-gp s ubset 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) s ubset 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 t yrosine kinases, and alterations of c-Cbl to LAT ratios in the P-gp(high) s ubset may thus contribute to the hyporesponsiveness of this age-dependent, anergic memory cell population.