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.