A central question in autoimmunity is the mechanism of T cell help for autoantibody production. For responses to exogenous Ag, T-B collaboration is restricted by MHC class II molecules. To determine whether T cell help that leads to autoantibodies in murine SLE is also MHC-restricted, we have constructed bone marrow chimeras with Ig heavy chain (lgh) allotype- and I-A-congenic donor B6/lpr mice and I-A-congenic recipients. Developing T cells were thus positively selected in the host thymus to interact with B cells bearing I-A of one haplotype or the other. Additional control host mice were heterozygous for I-A expression, allowing T helper cell selection for both I-A haplotypes. Five months after reconstitution, serum total IgG2a, IgM, IgG2a antichromatin, and IgM rheumatoid factor were quantitated by allotype-specific ELISA. Data showed that whereas substantial numbers of B cells were present from both donor strains in all mice, autoantibody production was overwhelmingly from those donor B cells expressing the same I-A haplotype as the host. Sera from the I-A heterozygous control recipient group had roughly equal quantities of autoantibodies of both allotypes, as expected. The finding of MHC class II restriction implies that the T cell help that drives autoantibody production in lpr mice is delivered through cognate (cell-to-cell) interactions and not by soluble factors alone.