KLRG1, Cadherins and their Interactions

The killer cell lectin‐like receptor G1 (KLRG1) is a unique inhibitory receptor expressed on a phenotypically mature subset of resting NK cells as well as effector memory CD8+ T cells. KLRG1 is a C‐type lectin inhibitory receptor that contains an immunoreceptor tyrosine‐based inhibitory motif (ITIM) in its cytoplasmic domain. It has been demonstrated that engagement of the KLRG1 molecule inhibits NK cell functions. KLRG1 ligands have been recently identified and are members of the broadly expressed cadherin family, E, N, and R‐cadherin. In this study, we attempt to elucidate the consequences of cadherin engagement by KLRG1 as well as KLRG1 engagement by cadherin. We find that KLRG1 engagement by E‐cadherin induces a moderate but significant inhibition of TCR signaling. In addition, we showed that recombinant extra cellular domain of E‐cadherin blocks KLRG1 tetramer binding to cadherin expressing cells. Interestingly, upon analysis of E‐cadherin mutants, we found that E‐cadherin cell surface expression is regulated by its cytoplasmic domain. Finally, we found that E‐cadherin engagement by KLRG1 influences the dynamics of E‐cadherin expression. Taken together, our data suggest that immune receptor interaction with cadherin may have an impact not only on immune cells such as NK cells but also on cells expressing cadherin such as epithelial cells. Supported by NIH Grant AI58181.