CD8αα homodimers function as a coreceptor for KIR3DL1

Cluster of differentiation 8 (CD8) is a cell surface glycoprotein, which is expressed as 2 forms, alpha alpha homodimer or alpha beta heterodimer. Peptide-loaded major histocompatibility complex class I (pMHC-I) molecules are major ligands for both forms of CD8. CD8 alpha beta is a coreceptor for the T cell receptor (TCR) and binds to the same cognate pMHC-I as the TCR, thus enabling or augmenting T cell responses. The function of CD8 alpha alpha homodimers is largely unknown. While CD8 alpha beta heterodimer is expressed exclusively on CD8(+) T cells, the CD8 alpha alpha homodimer is present in subsets of T cells and human natural killer (NK) cells. Here, we report that the CD8 alpha alpha homodimer functions as a coreceptor for KIR3DL1, an inhibitory receptor of NK cells that is specific for certain MHC-I allotypes. CD8 alpha alpha enhances binding of pMHC-I to KIR3DL1, increases KIR3DL1 clustering at the immunological synapse, and augments KIR3DL1-mediated inhibition of NK cell activation. Additionally, interactions between pMHC-I and CD8 alpha alpha homodimers regulate KIR3DL1(+) NK cell education. Together, these findings reveal another dimension to the modulation of NK cell activity.