Abnormal antigen receptor-initiated signal transduction in lpr T lymphocytes.

The CD4-, CD8- double-negative (DN) T cells that accumulate in an age-dependent manner in peripheral lymphoid organs of lpr-homozygous mice display deficient activation in response to signals initiated by the antigen-specific T cell receptor (TCR)/CD3 complex. Abnormalities which could contribute to this defect include low expression and rapid TCR/CD3 modulation, loss of CD4, CD8, CD2 and Ly-6.2, aberrant expression of CD45, and constitutive elevations of inositol phospholipid turnover, tyrosine phosphorylation, and expression of the p59fyn protein tyrosine kinase (PTK) and a few other protooncogenes. These properties strongly suggest that DN lpr T cells are chronically activated in vivo, perhaps by some self antigen(s), rendering them refractory to additional in vitro stimulation. Deficient activation of these cells is, therefore, most likely a secondary consequence of the Fas defect whose primary effect is allowing these aberrant cells to escape from the thymus and expand in the periphery.