(A) CD8⁺ T cells in individuals whose genotype confers greater numbers of functional pairs of inhibitory KIRs (iKIRs) and cognate class I HLA ligands exhibit longer lifespans during in vivo labeling experiments. (B) iKIRs predict increased T cell lifespan via the formation of functional HLA pairs. Possible indirect mechanisms by which the number of KIR-HLA pairs could prolong the CD8⁺ T cell lifespan and antiviral immunity include NK cell killing and the effects of CD4⁺ T cells and DCs. An individual possessing one KIR-HLA pair is predicted to have less inhibition of KIR-expressing NK cells and CD8⁺ Tregs than do those possessing four functional KIR-HLA pairs. NK cells directly suppress CD8⁺ T cell survival or indirectly suppress CD8⁺ T cells through the modulation of CD4⁺ T cells via help. DCs can also indirectly promote CD8⁺ T cell survival via priming. Fewer functional KIR-HLA pairs lead to shorter T cell lifespans and reduced antiviral immunity. In contrast, another individual possessing four KIR-HLA pairs that exert strong suppression of NK cell killing and KIR⁺CD8⁺ Treg function could facilitate longer T cell lifespans and improved antiviral immunity.