Cutting Edge: Identification of E-Cadherin as a Ligand for the Murine Killer Cell Lectin-Like Receptor G1

Abstract

The killer cell lectin-like receptor G1 (KLRG1) is expressed by NK cells and by T cells. In both humans and mice, KLRG1 identifies Ag-experienced T cells that are impaired in their proliferative capacity but are capable of performing effector functions. In this study, we identified E-cadherin as a ligand for murine KLRG1 by using fluorescently labeled, soluble tetrameric complexes of the extracellular domain of the murine KLRG1 molecule as staining reagents in expression cloning. Ectopic expression of E-cadherin in B16.BL6 target cells did not affect cell-mediated lysis by lymphokine-activated NK cells and by CD8 T cells but inhibited Ag-induced proliferation and induction of cytolytic activity of CD8 T cells. E-cadherin is expressed by normal epithelial cells, Langerhans cells, and keratinocytes and is usually down-regulated on metastatic cancer cells. KLRG1 ligation by E-cadherin in healthy tissue may thus exert an inhibitory effect on primed T cells.

NK Cell Maturation and Peripheral Homeostasis Is Associated with KLRG1 Up-Regulation

“…Recently, E-, R-, and Ncadherins, found on Langerhans cells, keratinocytes, and epithelial cells, were identified as ligands for KLRG1 (14 -16). Indeed, Ecadherin was shown to inhibit both Ag-specific proliferation of KLRG1 ϩ T cells and cytotoxic potential (15) while also inhibiting NK cell cytotoxicity (16), suggesting that this interaction is physiologically important. If this is true, induction of KLRG1 expression whether during viral responses or normal development could serve as a mechanism to inhibit NK cell growth, function, and potential immunopathology in the absence of Ag exhaustion.…”

“…Given the fact that KLRG1 can act as an inhibitory receptor (15,16), sorting NK cells using an anti-KLRG1 Ab may subject KLRG1 ϩ NK cells to inhibition. To overcome this effect, we analyzed the expression of NK cell surface markers to identify proteins differentially expressed from KLRG1.…”

Different inhibitory capacities of human and mouse KLRG1 are linked to distinct disulfide‐mediated oligomerizations

“…Given that E-cadherin also binds KLRG1 with low affinities, it is obvious to speculate about a contribution of multivalent KLRG1/E-cadherin engagements to the strengthening of cell-cell interactions. To analyze this hypothesis, we created an mKLRG1 molecule with Y 7 F and P 16 T replacements in the ITIM and PxxP motif. In addition, we designed an mKLRG1-Y 7 F/P 16 T molecule also carrying the aa substitution C 62 Q that limits oligomer formation to disulfide-linked dimers.…”

“…The C-type lectin-like domain of KLRG1 interacts with a highly conserved region of E-, N-and R-cadherins [16][17][18][19][20]. Upon ligation, KLRG1, which contains an ITIM in its cytoplasmic domain, recruits the phosphatases SHP-2 and SHIP-1 [4,21] To compare the inhibitory capacities of human and mouse KLRG1, we generated A5 cells expressing these molecules on the cell surface to the same extent (Fig.…”

“…Viral, bacterial, and parasitic infections induce KLRG1 expression in NK and T cells [8][9][10][11]. KLRG1 is frequently used to identify highly differentiated T cells including short-lived effector CD8 + T cells generated in the acute phase of infection [7,8,[12][13][14][15].The C-type lectin-like domain of KLRG1 interacts with a highly conserved region of E-, N-and R-cadherins [16][17][18][19][20]. Upon ligation, KLRG1, which contains an ITIM in its cytoplasmic domain, recruits the phosphatases SHP-2 and SHIP-1 [4,21] To compare the inhibitory capacities of human and mouse KLRG1, we generated A5 cells expressing these molecules on the cell surface to the same extent (Fig.…”