In this study, we investigated whether Peyer's patch-derived T-cell subsets participate in vitro in self major histocompatibility (MHC) class II antigen (Ag)-mediated immunoregulatory circuits for gut-mucosal IgA isotype selection in the presence of Peyer's patch (PP)-derived syngeneic surface immunoglobulin M (sIgM)-bearing B cells. When fresh ( in vitro unstimulated) sIgM-bearing B cells were cocultured with fresh, PP-derived L3T4 + Vicia villosa-nonadherent (VV −) T cells (T helper (Th) cells), the production of all class-specific immunoglobulins (Ig), but, in particular, IgA, was enhanced two- to sixfold. This augmented Ig production was, however, reduced by nearly 50% when fresh PP-derived Lyt 2 + VV − T cells (suppressor T cells) were added. Furthermore, addition of PP-derived L3T4 + VV + and Lyt 2 + VV + T cells abrogated, by nearly 100%, the suppression induced by the Lyt 2 + VV − T cells (contrasuppression). When lipopolysaccharide (LPS)-stimulated, PP-derived sIgM-bearing B cells were cocultured with the Th cells, the production of each class-specific Ig was similarly enhanced, but Ig levels exceeded those obtained with cultures of the unstimulated B cells ( P < 0.001). Anti-I-A or anti-I-E monoclonal antibody (mAb) inhibited the induction of each immunoregulatory T-cell effector activity ( P < 0.001), and anti-I-A/E inhibited it synergistically. Thus, unstimulated fresh PP-derived T cells appear to be activated and then to exert T-cell effector functions in the sequential development of helper, suppressor, and contrasuppressor immunoregulatory networks in the presence of PP-derived sIgM B cells and, particularly, LPS-preactivated sIgM B cells. Based on the blocking effect of anti-I-A and/or anti-I-E mAb on the induction of each T-cell-mediated immunoregulatory function in class-specific Ig production, it appears that the autoreactive (self MHC class II Ag-reactive) activation of PP T cells evoked by Ia Ag on PP sIgM B cells largely controls mucosal IgA production by the latter cells. Furthermore, this immunoregulation by autoreactive effector T cells, especially the L3T4 + VV − helper T cell, may play a significant role in vivo in gut-mucosal IgA isotype production.