KLRG1 activity is regulated by association with the transferrin receptor

The killer cell lectin-like receptor G1 (KLRG1) is a cadherin-binding inhibitory receptor expressed by NK cells and differentiated T cells. Here, we surprisingly found that a fraction of KLRG1 molecules expressed in the murine A5 T-cell line and in IL-2-activated NK cells forms disulfide-linked heteromers with the transferrin receptor (TfR). Fluorescence microscopy additionally revealed substantial colocalization of KLRG1 and TfR in intracellular compartments and on the cell surface. TfR expression in resting lymphocytes is known to be low but it is strongly upregulated in proliferating cells. Intriguingly, our data further demonstrate that the inhibitory activity of KLRG1 is decreased in T cells expressing high levels of TfR, indicating that association of KLRG1 with TfR hinders KLRG1-mediated silencing. This implies that proliferating TfR(high) KLRG1(+) lymphocytes may respond strongly to activation signals even in the presence of KLRG1 ligands, whereas resting TfR(low) cells may be efficiently silenced via KLRG1.