We have investigated the role of MHC class I products and CD8 T cells in regulating Ab responses using β 2-microglobulin deficient (β 2 m−/−) mice. β 2 m−/− mice produced stronger IgM and IgG responses than did control β 2 m+/+ mice to both cellular and viral Ags. These Ab responses could be suppressed by infusion of activated B cells from β 2 m+/+ mice. Further investigation showed that the β 2 m-associated molecule on activated B cells that induced CD8 suppression was Qa-1 and that the Th2 component of CD4 cells was most affected by CD8-suppressive activity. Our findings suggest a novel pathway of Th inhibition in which B cell presentation of Qa-1-associated peptides stimulates CD8 suppressive activity.