Although persistent antigen plays a significant role in sustaining CD8+ Tex for terminal differentiation in the tumor, other early events in CD8+ T cell activation may also be critical for the initial programming of exhaustion in the periphery or specialized tumor niches, including TCR signal quality/strength (NFAT versus NFAT/AP-1 signaling, discussed below), co-stimulation, IL-2 availability (with associated CD4+ T cell helper signals), and inflammatory cues in the first few divisions (Figure 3A) (1, 10, 19–22). This evidence concerns the gene CD4 and neoplasm.