CD8 as co-receptor: Not just the TCR

Abstract

CD8αβ is a co-receptor for the T cell receptor (TCR), and is classically known to bind to the same cognate peptide-loaded major histocompatibility complex class I molecules (pMHC-I) as the TCR, thus enabling or augmenting T cell responses. Our recent findings show that peptide-deficient forms of MHC class I bind CD8 with high affinity. While peptide-deficient conformers of HLA-B*35:01 did not directly activate CD8+ T cells, they enhanced CD8+ T cell adhesion to target cells in a CD8-dependent manner and increased cognate peptide-induced CD8+ T cell activation 1 . CD8αα homodimers are present in subsets of T cells and human NK cells. The function of CD8αα homodimer in such contexts is largely unknown. We report that CD8αα 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 CD8αα homodimers regulate KIR3DL1+ NK cell education. Together, these findings reveal new dimensions of CD8-dependent modulation of immune cell activity.