AbstractThe I‐A subregion mutant B6.C‐H‐2bm12(bm12) and the C57BL/6 parent were used to examine the role of the Ia‐1 gene product as a restriction element in the antibody response to sheep red blood cells (SRBC). Using anin vitroculture system, it was shown that cooperation between histocompatible T cells, B cells and macrophages was required to generate a secondary IgM response to SRBC. The alteration in the Ia‐1 gene in bm12 altered the ability of bm12 T cells to collaborate with C57BL/6 B cells, but not with C57BL/6 macrophages. Similarly, C57BL/6 T cells could not collaborate with bm12 B cells. The mutation in bm12 did not affect the ability of T cells to interact with C57BL/6 macrophages, eitherin vitroorin vivo, or of bm12 macrophages to interact with C57BL/6 T cells. Thus in this system, the Ia‐1 gene product restricts T‐B cell interaction but not T cell‐macroph