ABNORMAL LPR DOUBLE-NEGATIVE T-CELL FAILS TO PROLIFERATE IN-VIVO

Mice homozygous for the autosomal recessive gene lpr develop marked ly mphadenopathy and a systemic autoimmune disease resembling human syste mic lupus erythematosus. The enlarged nodes are dominated by T cells w ith an unusual surface phenotype: dull Thy-1(+), dull CD3(+), CD4(-), CD8(-), B220(+) (double-negative T cells or DNTs). Despite their massi ve accumulation in vivo, these cells fail to proliferate in response t o conventional T-cell mitogens in vitro. The identification of the lpr mutation as a defect in the Fas apoptosis receptor gene suggests that DNT accumulation may result from abnormal persistence rather than ove rproliferation. To test in vivo whether DNTs persist abnormally or hav e a capacity to differentiate into single-positive T cells, we have pe rformed cell transfer experiments between congenic strains of lpr and +/+ mice differentially marked by expression of the Ly-1 or Thy-1 alle les. Although transferred lpr lymph node cells were mostly DNTs at the time of injection, most recovered cells of donor origin were single p ositive, particularly CD8(+), at all time points after transfer. Furth ermore, transfer of purified DNTs resulted in recovery of relatively f ew cells of donor origin. Transfer of lpr T cells enriched for CD8 exp ression confirmed the preferential survival of this subset. Thus, DNTs are a surprisingly transient population and have little capacity for transformation to single positives. This would suggest that DNTs are c onstantly being renewed, perhaps from CD4(+) and CD8(+) precursors. (C ) 1995 Academic Press, Inc.