PI3K plays crucial roles in the immune system. Mice deficient for p85 alpha, a major regulatory subunit of class IA PI3K, show various defects and alterations in B cells, mast cells, macrophages, and DCs, and peripheral T cells are reportedly normal, at least in vitro. In normal mice, long-term exposure to a SAg, SEA, in vivo induced a high level of the protracted expansion of SEA-reactive V beta 3(+)CD4(+) T cells, whereas the same treatment induced T cell expansion in p85 alpha-deficient mice but to a much lesser extent than in normal mice. However, mixed bone marrow chimera mice, which have normal and p85 alpha-deficient T and B cells, demonstrated equal responses of both T cells following stimulation with a SEA pump. In reciprocal cotransfer experiments of T and B cells from normal and p85 alpha-deficient mice into Rag2-deficient mice, followed by SEA stimulation, p85 alpha-deficient T cells revealed much higher proliferative capacity in the presence of normal B cells than did normal T cells with p85 alpha-deficient B cells. Histologically, a marked B cell reduction was observed in the follicles and MZ of the spleen, and DCs accumulated in the MZ. In addition, p85 alpha-deficient B cells had a low level of MHC class II expression. Collectively, these data suggested that the PI3K p85 alpha subunit alters the SAg presentation capacity of B cells and indirectly modulates the magnitude of the T cell response, which may affect the protection against SEA-containing bacteria. J. Leukoc. Biol. 87: 493-500; 2010.