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Single-Cell Analyses Reveal Two Defects in Peptide-Specific Activation of Naive T Cells from Aged Mice¹

Gonzalo G. Garcia^* and Richard A. Miller^2,*,,

^* Department of Pathology, University of Michigan School of Medicine, University of Michigan Institute of Gerontology, and Ann Arbor Department of Veteran Affairs Medical Center, Ann Arbor, MI 48109

Confocal fluorescent microscopy was used to study redistribution of membrane-associated proteins in naive T cells from young and old mice from a transgenic stock whose T cells express a TCR specific for a peptide derived from pigeon cytochrome C. About 50% of the T cells from young mice that formed conjugates with peptide-pulsed APC were found to form complexes, at the site of binding to the APC, containing CD3, linker for activation of T cells (LAT), and Zap-70 in a central area and c-Cbl, p95^vav, Grb-2, PLC, Fyn, and Lck distributed more uniformly across the interface area. Two-color staining showed that those cells that were able to relocalize c-Cbl, LAT, CD3, or PLC typically relocalized all four of these components of the activation complex. About 75% of conjugates that rearranged LAT, c-Cbl, or PLC also exhibited cytoplasmic NF-AT migration to the T cell nucleus. Aging had two effects. First, it led to a diminution of 2-fold in the proportion of T cell/APC conjugates that could relocalize any of the nine tested proteins to the immune synapse. Second, aging diminished by 2-fold the frequency of cytoplasmic NF-AT migration among cells that could generate immune synapses containing LAT, c-Cbl, or PLC. Thus naive CD4 T cells from old mice exhibit at least two separable defects in the earliest stages of activation induced by peptide/MHC complexes.

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