Technical Abstract: The currently accepted model for superantigen (SAg )induced T cell activation suggests that SAg, without being processed, cross links both MHC class II, from Antigen Presenting Cells (APC), and V-beta, from T-cell receptor (TCR), initiating nonspecific T-cell activation. This T-cell proliferation induces a massive cytokine release associated with several human diseases. It is thought that murine CD4+ T cells do not express MHC class-II molecules. However, we discovered that a subtype of mouse naïve CD4+ T cells expresses MHC class II on their cell surface and that these CD4+ T cells can perform the role of both APC and T cells, able to present Staphylococcal enterotoxin A (SEA) to itself or neighboring CD4+ T cells via MHC class II, thus inducing massive CD4+ T cell proliferation. Treatment with neutralizing anti MHC class II antibody inhibits this CD4+ T cell proliferation response. The fact that murine CD4+ T cells express MHC class II offers new insight about SAg activity. Based on our findings, we propose revising and extending previous models for SAg induced T cell activation, altering previous models of MHC class II restriction of T cell responses to SEA as well as the requirement for SAg processing.