BETA(2)-MICROGLOBULIN DEPENDENCE OF THE LUPUS-LIKE AUTOIMMUNE SYNDROME OF MRL-LPR MICE

MRL-lpr/lpr mice develop a distinctive immunologic disease characteriz ed by accumulation of unusually large numbers of T cells in the periph eral lymphoid organs. Most of the accumulating T cells express an alph a beta-TCR but are peculiar in that they express neither CD4 nor CD8 c o-ligands. Concurrent with lymphoaccumulation of such double negative (DN) T cells, MRL-lpr/lpr mice develop a lethal systemic lupus erythem atosus-like autoimmune syndrome. This study focuses on the role of MHC class I molecules in this latter pathologic process. Highly backcross ed class I molecule-deficient MRL and MRL-lpr mice carrying a function ally defective allele of the gene beta(2)-microglobulin (B2m) were pro duced. Class I-deficient MRL-lpr/lpr mice demonstrated a substantial r eduction in DN T cells, confirming other reports indicating that most DN T cells arise from progenitors positively selected on MHC class I m olecules. Significantly, class I-deficient MRL-lpr/lpr mice also demon strated a diminution of every autoimmune disease indicator analyzed in cluding hypergammaglobulinemia; autoantibodies including anti-DNA, ant i-Smith antigen, and rheumatoid factor; and glomerulonephritis. The re sults indicate that class I-dependent T cells are crucial not only for the development of DN T cells, but for multiple features of the MRL-l pr/lpr systemic lupus erythematosus syndrome. Moreover, the pattern of hypergammaglobulinemia suggests that the requirement for MHC class I proteins is restricted temporally to later stages of the disease.