Human CD94-NKG2 heterodimeric receptors have either inhibitory or activating effects on natural killer (NK) cells depending on the NKG2 family member. CD94-NKG2A associates with the SHP1 phosphatase through the immunoreceptor tyrosine-based inhibitory motif (ITIM) of NKG2A and inhibits NK cell activation. In contrast, CD94-NKG2C, CD94-NKG2E, and CD94-NKG2H, which lack a cytoplasmic ITIM, associate with the immunoreceptor tyrosine-based activation motif (ITAM)-containing Dap12 protein and function as activating receptors. Heterodimers of human CD94-NKG2A, C, E, or H recognize human leukocyte antigen (HLA)-E, while the corresponding mouse heterodimers recognized Qa1b. Similar to the CD94-NKG2 receptors, mouse NKG2I/Klre-1 forms a heterodimeric complex with KLRI1 or KLRI2, which either inhibits or promotes NK cell activation, respectively.