Figure 3. Is a 'two-signal' model of T cell activation still tenable? Signals emanating from the TCR (or the BCR) and the optional signals originating from a vast array of cell surface context detectors converge on intracytoplasmic coincident detectors.

Among the surface context detectors, much attention has focused on the CD28 costimulator. However, signals originating from the antigen receptor core can also be 'tuned' by many costimulators (such as CD5, CD19, NKG2D or integrins) and coinhibitors (such CD5, CD22, FcγRIIb or KIRs). The CD8-CD4 coreceptors constitute intrinsic components of the TCR sensor⁵⁷. It remains a daunting task to understand how the antigen-receptor signaling pathways are regulated through the summation of this multitude of positive and negative inputs.