NOVEL IMMUNOREGULATORY B-CELL PATHWAYS REVEALED BY LPR-+ MIXED CHIMERAS

lpr, a murine mutation of the Fas apoptosis receptor, causes lymphaden opathy and autoantibody production, with lymphadenopathy primarily due to a population of CD4(-)CD8(-)B220(+) T cells, Previous in vice expe riments, in which lpr and normal bone marrow cells were coinfused into lpr hosts, have demonstrated that only T cells of lpr origin accumula ted abnormally and only B cells of lpr origin produced autoantibodies. Moreover, in these chimeras, B cells of normal origin were unable to respond to conventional, T cell-dependent exogenous Ag, To address the role of lpr B cells in regulation of lpr autoimmunity, we have prepar ed lpr-+ mixed chimeras and selectively eliminated lpr B cells using a llele-specific, mAb treatment, thus allowing normal B cells to develop in an environment with lpr T tells, From these data, we arrived at fo ur major conclusions: I) Compared with control-treated chimeric mice, lpr B cell-depleted mice! had greatly reduced total lymph node cell co unts; 2) the T cells were derived equally from normal and lpr donors, and the percentage of lpr-derived CD4(-)CD8(-) T cells was greatly red uced; 3) despite the presence of the remaining lpr T cells, no autoant ibodies were produced by the normal derived B cells; and 4) lpr T cell s without lpr B cells were unable to prevent a normal B cell response to conventional Ag, These data demonstrate that B cells can play a cri tical and expansive regulatory role, not only for T cells, but for oth er B cells as well.