Antigen-specific suppression to poly(Glu50-Tyr50) (GT) is under the control of two complementary immune suppressor (Is) genes located in the major histocompatibility (H-2) complex of the mouse. Suppressor strains of mice produce both suppressor T (Ts) cells and Ts-derived suppressor factors (TsF) that bear antigenic determinants of the I-J subregion of the H-2 complex. Nonsuppressor strains of mice, on the other hand, are not suppressed by GT preimmunization. These nonsuppressor mice, however, can be classified according to those that lack the ability to make GT-specific T cell-derived suppressor factor (GT-TsF) after GT injection (i.e., H-2a, I-Jk mice) and those that lack the ability to be suppressed by the appropriate GT-TsF (i.e., H-2b,g2, I-Jb mice). In the present study, we demonstrate that (H-2a x H-2b,g2)F1 hybrid mice produce distinct GT-specific suppressor factors of both parental I-J haplotypes. Moreover, only the I-Jb-bearing GT-TsF derived from these F1 hybrid mice is able to induce second-order suppressor cells (Ts2). This is consistent with the observation that injection of GT-TsF1 derived from C57BL/6 (I-Jb) mice into A/J (I-Jk) mice leads to the production of an antigen-specific I-Jk GT-TsF2. Our results suggest that Is gene complementation occurs through a different cellular mechanism that was previously observed for Ir gene complementation. Further, we show that complementing (non-suppressor X nonsuppressor)F1 hybrid mice produce an I-Jb (and not an I-Jk) GT-TsF1 and an I-Jk (not an I-Jb) GT-TsF2, thus suggesting a heterogeneity of Ia loci within the I-J subregion. Data presented in the present study suggest that there may be even more heterogeneity within the I-J subregion than has has been heretofore reported with regard to I-J expression on Ts.

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