CD2(-)CD4(-)CD8(-) LYMPH-NODE T-LYMPHOCYTES IN MRL LPR LPR MICE ARE DERIVED FROM A CD2(+)CD4(+)CD8(+) THYMIC PRECURSOR

MRL lpr/lpr (lymphoproliferative, lpr) mice demonstrate an age-depende nt lymphoproliferation and development of autoimmunity. Characteristic of the lymphoproliferation in these mice is the accumulation of large numbers of CD4-CD8- (CD4-8-), CD3+ T lymphocytes in their lymph nodes . The development of the CD4-8- cells, which also aberrantly express B 220 and CD44 (Pgp-1) but are CD2-, has been shown to be thymus depende nt. An unusual feature of lpr CD4-8- T lymphocytes is that although th ey appear unresponsive to stimulation, as defined by proliferation and IL-2 production, they have undergone thymic negative selection. As th ymic deletion normally occurs at the CD4+CD8+ (CD4+8+) stage, this rai ses the dilemma that lpr CD4-8- T lymphocytes have either previously b een CD4+8+, or they are able to undergo thymic selection as CD4-8- cel ls. We have addressed this question by examining the methylation statu s of the CD8 gene in MRL lpr CD4-8- lymph node cells. Demethylation of the CD8 gene has been shown to be an indicator of previous CD8 expres sion. We find that the CD8 gene in lpr CD4-8- lymph node cells, as wel l as in the abnormal B220+CD4-8- lpr thymocytes, is demethylated, sugg esting that these cells have previously expressed CD8. In addition, we find that the lpr CD4+8+ thymocyte population contains an increased p ercentage of atypical B220+, CD44+ cells that are virtually all CD2+. Taken together, these data are consistent with the lpr CD2-CD4-8- popu lation of LNC having arisen from a CD2+CD4+8+ thymic stage of differen tiation.