<jats:title>Abstract</jats:title> <jats:p>The recognition of foreign antigens by T cells is accomplished through the binding of the T cell receptor (TCR) in collaboration with co-receptor (CD4 or CD8) recognition of MHC. It is clear that CD4 and CD8 function by binding to their cognate MHCs and by delivering the kinase Lck to the TCR complex for initiation of signaling, however, the mechanistic details of this process remain unclear. For example, it remains unknown if co-receptors must engage the same MHC as the TCR, or if engagement of a nearby non-cognate MHC molecule is sufficient to initiate signaling. To examine the details of co-receptor function, we used a class II MHC specific TCR system consisting of a wild-type (KD 20 μM) and high-affinity variant (KD 25 nM). A panel of T cell hybridomas was generated expressing either the wild-type or high-affinity TCR paired with either the CD4 or CD8 co-receptor. The low-affinity, but not the high-affinity, TCR required cognate CD4 for activity. Unexpectedly, non-cognate CD8 was able to enhance the activity of the low-affinity TCR, and CD8:class I MHC interactions were required for activity mediated by the high-affinity TCR. Unexpectedly, CD8 also operated by preventing apoptosis of the antigen presenting cells (APCs). These data show that CD8 can act by binding to non-cognate MHC, and that its functions extend to the prevention of apoptosis of APCs. The findings thus provide a framework for a new model of co-receptor function.</jats:p>