Our previous studies indicated that cloned T cells obtained from Peyer's patches (PP) (Lyt-1+, 2-, Ia+, and H-2K/D+) evoked immunoglobulin (Ig) class switching of PP B cells from sIgM to sIgA cells in vitro; however, these switch T cells could not in themselves provide optimal help for the differentiation of postswitch sIgA-bearing PP B cells to IgA-secreting cells. Thus, in the present report we described studies focused on mechanisms regulating terminal differentiation of the postswitch PP sIgA-bearing B cells. First, to explore the effect of T cell-derived B cell differentiation factor(s) (BCDF) and macrophage factor(s) (MF) on the terminal maturation of PP B cells, LPS-stimulated PP B cells were co-cultured for 7 d with cloned T cells in the presence or absence of the above factors. In the absence of PP cloned T cells the BCDF and MF had only a modest effect on IgA production, whereas in the presence of PP, but not spleen cloned T cells, IgA production was increased. Next, to investigate the effect of T cells derived from a gut-associated lymphoid tissue (GALT), mesenteric lymph nodes (MLN), as well as from spleen on terminal differentiation of postswitch sIgA PP B cells, LPS-driven PP B cells were precultured with the cloned T cells to induce a switch to sIgA, and subsequently cultured with MLN or spleen T cells or a Lyt-2+-depleted T cell subset in the presence of a T-dependent polyclonal mitogen, staphylococcal protein A. Alternatively, in the second culture period BCDF alone was added, instead of T cells and protein A. Here it was found that B cells pre-exposed to switch T cells from PP, but not spleen, were induced to produce greatly increased amounts of IgA in the presence of protein A and T cells or a Lyt-2+-depleted T cell subset as well as in the presence of BCDF alone. Furthermore, in the presence of BCDF alone many B cells expressed cytoplasmic IgA. These observations strongly support the view that the terminal differentiation of postswitch sIgA B cells is governed by helper T cells and macrophages, or factors derived from such cells. Such cells or factors do not affect preswitch B cells.