Molecular Basis for E-cadherin Recognition by Killer Cell Lectin-like Receptor G1 (KLRG1)

The killer cell lectin-like receptor G1, KLRG1, is a cell surface receptor expressed on subsets of natural killer (NK) cells and T cells. KLRG1 was recently found to recognize E-cadherin and thus inhibit immune responses by regulating the effector function and the developmental processes of NK and T cells. E-cadherin is expressed on epithelial cells and exhibits Ca2+-dependent homophilic interactions that contribute to cell-cell junctions. However, the mechanism underlying the molecular recognition of KLRG1 by E-cadherin remains unclear. Here, we report structural, binding, and functional analyses of this interaction using multiple methods. Surface plasmon resonance demonstrated that KLRG1 binds the E-cadherin N-terminal domains 1 and 2 with low affinity (Kd ∼7–12 μm), typical of cell-cell recognition receptors. NMR binding studies showed that only a limited N-terminal region of E-cadherin, comprising the homodimer interface, exhibited spectrum perturbation upon KLRG1 complex formation. It was confirmed by binding studies using a series of E-cadherin mutants. Furthermore, killing assays using KLRG1+NK cells and reporter cell assays demonstrated the functional significance of the N-terminal region of E-cadherin. These results suggest that KLRG1 recognizes the N-terminal homodimeric interface of domain 1 of E-cadherin and binds only the monomeric form of E-cadherin to inhibit the immune response. This raises the possibility that KLRG1 detects monomeric E-cadherin at exposed cell surfaces to control the activation threshold of NK and T cells. The killer cell lectin-like receptor G1, KLRG1, is a cell surface receptor expressed on subsets of natural killer (NK) cells and T cells. KLRG1 was recently found to recognize E-cadherin and thus inhibit immune responses by regulating the effector function and the developmental processes of NK and T cells. E-cadherin is expressed on epithelial cells and exhibits Ca2+-dependent homophilic interactions that contribute to cell-cell junctions. However, the mechanism underlying the molecular recognition of KLRG1 by E-cadherin remains unclear. Here, we report structural, binding, and functional analyses of this interaction using multiple methods. Surface plasmon resonance demonstrated that KLRG1 binds the E-cadherin N-terminal domains 1 and 2 with low affinity (Kd ∼7–12 μm), typical of cell-cell recognition receptors. NMR binding studies showed that only a limited N-terminal region of E-cadherin, comprising the homodimer interface, exhibited spectrum perturbation upon KLRG1 complex formation. It was confirmed by binding studies using a series of E-cadherin mutants. Furthermore, killing assays using KLRG1+NK cells and reporter cell assays demonstrated the functional significance of the N-terminal region of E-cadherin. These results suggest that KLRG1 recognizes the N-terminal homodimeric interface of domain 1 of E-cadherin and binds only the monomeric form of E-cadherin to inhibit the immune response. This raises the possibility that KLRG1 detects monomeric E-cadherin at exposed cell surfaces to control the activation threshold of NK and T cells. Natural killer (NK) 3The abbreviations used are: NKnatural killerSLECshort lived effector CD8 T cellMES4-morpholineethanesulfonic acidSPRsurface plasmon resonanceAUCanalytical ultracentrifugationHSQCheteronuclear sequential quantum correlationPEphycoerythrin. 3The abbreviations used are: NKnatural killerSLECshort lived effector CD8 T cellMES4-morpholineethanesulfonic acidSPRsurface plasmon resonanceAUCanalytical ultracentrifugationHSQCheteronuclear sequential quantum correlationPEphycoerythrin. cells play a critical role in the innate immune system because of their ability to kill other cells. For example, NK cells can kill virus-infected cells and tumor cells without presensitization to a specific antigen, and they produce various cytokines, including interferon-γ and tumor necrosis factor-α (1Biron C.A. Nguyen K.B. Pien G.C. Cousens L.P. Salazar-Mather T.P. Annu. Rev. Immunol. 1999; 17: 189-220Crossref PubMed Scopus (1750) Google Scholar). NK cells are controlled by both inhibitory and activating receptors that are expressed on their surfaces (2Lanier L.L. Annu. Rev. Immunol. 2005; 23: 225-274Crossref PubMed Scopus (2192) Google Scholar). The killer cell Ig-like receptor, Ly49, CD94/NKG2, and paired Ig-like type 2 receptor families include both inhibitory and activating members and thus are designated as paired receptor families. On the other hand, some inhibitory receptors, including KLRG1 (killer cell lectin-like receptor G1), and activating receptors, such as NKG2D, also exist. The integration of the signals from these receptors determines the final functional outcome of NK cells. natural killer short lived effector CD8 T cell 4-morpholineethanesulfonic acid surface plasmon resonance analytical ultracentrifugation heteronuclear sequential quantum correlation phycoerythrin. natural killer short lived effector CD8 T cell 4-morpholineethanesulfonic acid surface plasmon resonance analytical ultracentrifugation heteronuclear sequential quantum correlation phycoerythrin. These inhibitory and activating receptors can also be divided into two structurally different groups, the Ig-like receptors and the C-type lectin-like receptors, based on the structural aspects of their extracellular regions. The Ig-like receptors include killer cell Ig-like receptors and the leukocyte Ig-like receptors, and the C-type lectin-like receptors include CD94/NKG2(KLRD/KLRC), Ly49(KLRA), NKG2D(KLRK), NKR-P1(KLRB), and KLRG1. Many of these immune receptors recognize major histocompatibility complex class I molecules or their relatives (2Lanier L.L. Annu. Rev. Immunol. 2005; 23: 225-274Crossref PubMed Scopus (2192) Google Scholar, 3Moretta L. Moretta A. Curr. Opin. Immunol. 2004; 16: 626-633Crossref PubMed Scopus (286) Google Scholar, 4Yokoyama W.M. Curr. Opin. Immunol. 1998; 10: 298-305Crossref PubMed Scopus (148) Google Scholar), but there are still many orphan receptors expressed on NK cells. KLRG1 was one such orphan receptor; however, E-cadherin was recently found to be a ligand of KLRG1 (5Ito M. Maruyama T. Saito N. Koganei S. Yamamoto K. Matsumoto N. J. Exp. Med. 2006; 203: 289-295Crossref PubMed Scopus (177) Google Scholar, 6Gründemann C. Bauer M. Schweier O. von Oppen N. Lässing U. Saudan P. Becker K.F. Karp K. Hanke T. Bachmann M.F. Pircher H. J. Immunol. 2006; 176: 1311-1315Crossref PubMed Scopus (125) Google Scholar). Although major histocompatibility complex-receptor interactions have been extensively examined, the molecular basis of non-major histocompatibility complex ligand-receptor recognition is poorly understood. KLRG1 is a type II membrane protein, with one C-type lectin domain in the extracellular region, one transmembrane region, and one immunoreceptor tyrosine-based inhibitory motif. KLRG1 is expressed on a subset of mature NK cells in spleen, lungs, and peripheral blood during normal development. KLRG1 expression is induced on the surface of NK cells during viral responses (7Robbins S.H. Tessmer M.S. Mikayama T. Brossay L. J. Immunol. 2004; 173: 259-266Crossref PubMed Scopus (83) Google Scholar, 8Robbins S.H. Nguyen K.B. Takahashi N. Mikayama T. Biron C.A. Brossay L. J. Immunol. 2002; 168: 2585-2589Crossref PubMed Scopus (115) Google Scholar). NK cells expressing KLRG1 produce low levels of interferon-γ and cytokines and have a slow in vivo turnover rate and low proliferative responsiveness to interleukin-15 (9Huntington N.D. Tabarias H. Fairfax K. Brady J. Hayakawa Y. Degli-Esposti M.A. Smyth M.J. Tarlinton D.M. Nutt S.L. J. Immunol. 2007; 178: 4764-4770Crossref PubMed Scopus (226) Google Scholar). Furthermore, KLRG1 is recognized as a marker of some T cell subsets, as follows. KLRG1 defines a subset of T cells, short lived effector CD8 T cells (SLECs), which are mature effector cells that express high levels of KLRG1 and cannot be differentiated into long lived memory CD8 T cells. In addition, memory precursor effector cells express low levels of KLRG1 and harbor the potential to become long lived memory CD8 T cells (10Joshi N.S. Cui W. Chandele A. Lee H.K. Urso D.R. Hagman J. Gapin L. Kaech S.M. Immunity. 2007; 27: 281-295Abstract Full Text Full Text PDF PubMed Scopus (1235) Google Scholar). Since SLECs exhibit stronger effector function than memory precursor effector cells, it is potentially beneficial, in terms of preventing harmful excess cytotoxicity, that SLECs express KLRG1 at a higher level to inhibit the immune response. Taken together, the expression of KLRG1 during the viral response and normal development might confer the inhibition of effector function and the regulation of NK and T cell proliferation (9Huntington N.D. Tabarias H. Fairfax K. Brady J. Hayakawa Y. Degli-Esposti M.A. Smyth M.J. Tarlinton D.M. Nutt S.L. J. Immunol. 2007; 178: 4764-4770Crossref PubMed Scopus (226) Google Scholar). E-cadherin plays a pivotal role in Ca2+-dependent cell-cell adhesion and also contributes to tissue organization and development (11Gooding J.M. Yap K.L. Ikura M. BioEssays. 2004; 26: 497-511Crossref PubMed Scopus (134) Google Scholar, 12Takeichi M. Science. 1991; 251: 1451-1455Crossref PubMed Scopus (2966) Google Scholar, 13Gumbiner B.M. J. Cell Biol. 2000; 148: 399-404Crossref PubMed Scopus (686) Google Scholar, 14Pokutta S. Weis W.I. Annu. Rev. Cell Dev. Biol. 2007; 23: 237-261Crossref PubMed Scopus (276) Google Scholar). E-cadherin is primarily expressed on epithelial cells, and its extracellular region consists of several domains that include cadherin motifs (15Overduin M. Harvey T.S. Bagby S. Tong K.I. Yau P. Takeichi M. Ikura M. Science. 1995; 267: 386-389Crossref PubMed Scopus (370) Google Scholar, 16Shapiro L. Fannon A.M. Kwong P.D. Thompson A. Lehmann M.S. Grübel G. Legrand J.F. Als-Nielsen J. Colman D.R. Hendrickson W.A. Nature. 1995; 374: 327-337Crossref PubMed Scopus (967) Google Scholar). These domains mediate Ca2+-dependent homophilic interactions to facilitate cell adhesion. When E-cadherins form cis- or trans-homodimers, they utilize their N-terminal regions as an interface, which can dock with domain 1 of another E-cadherin to form strand exchange (17Nose A. Tsuji K. Takeichi M. Cell. 1990; 61: 147-155Abstract Full Text PDF PubMed Scopus (410) Google Scholar). Therefore, the N-terminal region plays important roles in homophilic binding and cell adhesion. KLRG1 recognizes E-cadherins (and other class I cadherins), which are widely expressed in tissues and form tight adhesive cell-cell junctions, and Ito et al. (5Ito M. Maruyama T. Saito N. Koganei S. Yamamoto K. Matsumoto N. J. Exp. Med. 2006; 203: 289-295Crossref PubMed Scopus (177) Google Scholar) demonstrated that E-cadherin binding by KLRG1 inhibits NK cytotoxicity. Further, Gründermann et al. (6Gründemann C. Bauer M. Schweier O. von Oppen N. Lässing U. Saudan P. Becker K.F. Karp K. Hanke T. Bachmann M.F. Pircher H. J. Immunol. 2006; 176: 1311-1315Crossref PubMed Scopus (125) Google Scholar) showed that the E-cadherin-KLRG1 interaction inhibits the antigen-induced proliferation and induction of the cytolytic activity of CD8 T cells. Therefore, it is plausible that E-cadherin recognition by KLRG1, expressed on the surfaces of NK cells and T cells, may raise their activation thresholds by transducing inhibitory signals. Such an inhibition would prevent the excess injury of normal cells, which might result in inflammatory autoimmune diseases. KLRG1 may also have an important role in monitoring and removing cancer cells that lose E-cadherin expression. A recent report demonstrated that N-terminal domains 1 and 2 of E-cadherin are critical for KLRG1 recognition (18Rosshart S. Hofmann M. Schweier O. Pfaff A.K. Yoshimoto K. Takeuchi T. Molnar E. Schamel W.W. Pircher H. Eur. J. Immunol. 2008; 38: 3354-3364Crossref PubMed Scopus (54) Google Scholar); however, despite accumulating evidence supporting the functional importance of the E-cadherin-KLRG1 interaction, the molecular basis of this interaction is poorly understood. Here, we report that the N-terminal region of E-cadherin, comprising the dimer interface, is the binding site for KLRG1. This suggests that KLRG1 does not recognize the dimeric form of E-cadherin but rather recognizes the monomeric form, which is exposed on the cell surfaces of disrupted or infected cells. This may suppress excess immune responses. The plasmid pET15bEC-D1D2(His10Xa), encoding domains 1 and 2 of E-cadherin, with a His10 tag, a spacer sequence, and a Factor Xa recognition site at the N terminus (EC-D1D2(His10Xa)), and pET15bEC-D2D3(His10) encoding domains 2 and 3 (residues 109–332) with an additional His10 tag (EC-D2D3(His10)) were used to express recombinant proteins in Escherichia coli strain BL21 (DE3) pLysS. Soluble EC-D1D2(His10Xa) was subjected to Ni2+-nitrilotriacetic acid affinity chromatography (HisTrapFF, 5 ml; GE Healthcare), or the inclusion bodies of EC-D1D2(His10Xa) were dissolved in guanidine buffer (6 m guanidine HCl, 50 mm MES-NaOH, pH 6.5, 100 mm NaCl, 10 mm EDTA). To refold the recombinant protein, 10–20 mg of solubilized inclusion bodies were gradually diluted by the addition of refolding buffer (20 mm Tris-HCl, pH 7.9, 300 mm NaCl, 10% glycerol, 1 mm phenylmethylsulfonyl fluoride) at 4 °C, into a final volume of 1 liter. The was for 2 and was to by a system and an The was by chromatography GE EC-D1D2(His10Xa) was with Factor Xa to the The was designated as was by the of the The encoding the extracellular region (residues of KLRG1 was into to the plasmid The recombinant was expressed as inclusion bodies and was in a as and The was by chromatography For surface plasmon resonance a of KLRG1 was as (5Ito M. Maruyama T. Saito N. Koganei S. Yamamoto K. Matsumoto N. J. Exp. Med. 2006; 203: 289-295Crossref PubMed Scopus (177) Google Scholar). including the were dissolved in buffer mm pH mm NaCl, were with a KLRG1 was on the which been was used as a control cadherin were the KLRG1 protein, at a rate of 10 in buffer with 10 mm or 3 mm the The binding response at was by the response in the control cell from the response in The were using the and were by of the binding was using a analytical with an and cells. were at 4 °C, and were at and the of the and and one was were using the of the were in mm pH with 100 mm and monomeric KLRG1 were at a of without was expressed in E. coli the plasmid pET15bEC-D1D2(His10Xa), in 1 and was by the used for the KLRG1 was as The KLRG1 and proteins were both dissolved in the buffer mm pH mm NaCl, 3 mm EDTA). For the of KLRG1 binding to a series of heteronuclear sequential quantum correlation at μm), μm), μm), and were at were at and on with The were by were by the N. N. M. M. J. 1999; PubMed Scopus Google Scholar). and of were using a with as the of the as and in the of for were in buffer with 3 mm cell and NK cell NK expressing KLRG1, were as (5Ito M. Maruyama T. Saito N. Koganei S. Yamamoto K. Matsumoto N. J. Exp. Med. 2006; 203: 289-295Crossref PubMed Scopus (177) Google Scholar). The and cell were by T. of from E-cadherin cells was by M. Takeichi of and and was used to E-cadherin expression. of was from encoding the extracellular region of and M. E-cadherin was into the using and to produce These were into cells, using were used to cells. cells were with E-cadherin and to the expression of E-cadherin. were with a system and with KLRG1 was by KLRG1 with as N. M. K. W.M. Yamamoto K. J. Exp. Med. PubMed Scopus (83) Google Scholar). The of KLRG1 used in the binding studies was cells expressing E-cadherin were with KLRG1 or in 2 and cell and were by The KLRG1 reporter cell was as (5Ito M. Maruyama T. Saito N. Koganei S. Yamamoto K. Matsumoto N. J. Exp. Med. 2006; 203: 289-295Crossref PubMed Scopus (177) Google Scholar). The reporter cells were by cells expressing E-cadherin for at in and activity was by a using as The of cells cells expressing E-cadherin was using and cells expressing E-cadherin were with at for 5 in the cells were with effector cells in the or of in a for in the The expression of E-cadherin the cells from killing by cells, and the was by the interaction with 1 was to the and cells were on for were using the system and on N-terminal domains 1 and 2 of M. E-cadherin (residues with a His10 tag, a spacer sequence, and a Factor Xa recognition site at the N terminus were expressed in E. coli as a or inclusion The was using Ni2+-nitrilotriacetic acid and the inclusion bodies were by the For both the N-terminal were with Factor in the N-terminal as was by exchange A final of mg of was from 1 of N-terminal domains 2 and 3 of M. E-cadherin as 109–332) was also as inclusion bodies in E. coli and by the The was by the extracellular region of M. KLRG1 (residues was expressed in E. coli as inclusion KLRG1 was by the in a as E-cadherin. The was by chromatography A and and the final was 1 mg of KLRG1 from 1 of To the molecular interaction KLRG1 and E-cadherin, we using recombinant E-cadherins and E-cadherin and were the cells, in which KLRG1 been at a level of response a was on one of the cells, at a level to that of KLRG1. The response from the control was from response from the recombinant and the of these binding In with recent results that the of domain 1 or 2 in KLRG1 reporter cell assays (18Rosshart S. Hofmann M. Schweier O. Pfaff A.K. Yoshimoto K. Takeuchi T. Molnar E. Schamel W.W. Pircher H. Eur. J. Immunol. 2008; 38: 3354-3364Crossref PubMed Scopus (54) Google Scholar), that KLRG1 can to domains 1 and 2 of E-cadherin but not to domains 2 and 3 The interaction to a binding and its was at in the of This affinity is the of for other cell-cell recognition molecules Furthermore, the interaction in the of exhibited a of that binding was of of does not have a on KLRG1 binding and in These results that KLRG1 binding is on the N-terminal domain of E-cadherin. The that the interaction at To we of and KLRG1 were at a of The to the The molecular of the complex was which to the molecular of a complex monomeric KLRG1 and monomeric Furthermore, demonstrated and KLRG1 were the as for the complex at the of the complex not These results evidence for the binding of the to the binding site of KLRG1 on we an NMR perturbation was with KLRG1 at of and of the were were in the spectrum KLRG1 to as with the spectrum of These were at KLRG1, to a binding The acid were or upon the complex are to the N-terminal region of as in A and This result that KLRG1 can recognize the N-terminal region of The of the N-terminal region not have that showed To the results of the NMR binding was The of in were as using these showed that the cannot to KLRG1. In addition, both the and showed KLRG1 of these are in the N-terminal region of E-cadherin and with the results of the NMR The other including the to KLRG1 at levels that of the The are in of KLRG1 binding to and in a To the KLRG1 binding site on the N-terminal region of E-cadherin, KLRG1 binding to type or a series of E-cadherins and expressed on the cell surface was by cells expressing or E-cadherin were by and E-cadherin expression was confirmed by with as in KLRG1 was as The and to the KLRG1 These that KLRG1 recognizes a of the N-terminal region of E-cadherin that is for homophilic supporting the that KLRG1 can only to monomeric E-cadherin. the E-cadherin to the KLRG1 at levels with that of type KLRG1 reporter cell assays using the cell and cells expressing or The cells express a receptor that the extracellular and transmembrane regions of KLRG1 and the region of T cell receptor which can mediate the activating to expression. This cell also a reporter the control of the the E-cadherin binding to the KLRG1 can the expression. The and E-cadherin to expression In the and E-cadherins induced the expression of These results are with the and binding and that the N-terminal region of E-cadherin plays an role in To the N-terminal of E-cadherin NK cell we NK cell assays using the NK cell cells expressing or E-cadherin were used as cells in the killing which were as The expression of E-cadherin cells from killing by cells. This was in the of the of which inhibits the interaction and cells expressing E-cadherin not of killing by cells in the or of the not were using cells expressing the E-cadherin, with the binding and reporter cell On the other hand, cells expressing the and E-cadherins were by cells at levels both in the and of the These results that E-cadherin that binding also inhibition of killing by cells and These results that the N-terminal of E-cadherin are critical for the inhibition of NK cell cytotoxicity. E-cadherin is expressed by epithelial cells and Ca2+-dependent cell-cell adhesion. The N-terminal regions of are to play an important role in adhesion S. Weis W.I. Annu. Rev. Cell Dev. Biol. 2007; 23: 237-261Crossref PubMed Scopus (276) Google Scholar, A. Tsuji K. Takeichi M. Cell. 1990; 61: 147-155Abstract Full Text PDF PubMed Scopus (410) Google Scholar). The N-terminal region of E-cadherin can two In the with and In the the N-terminal region can dock with domain 1 of another cadherin to form an adhesive in which strand exchange E. J.M. J. Biol. 2007; PubMed Scopus Google Scholar). This that KLRG1 recognizes a of the N-terminal region of E-cadherin which with the homodimer In addition, cells expressing E-cadherin and not with KLRG1 or of KLRG1 reporter cell Further, the expression of the N-terminal E-cadherins on cells not inhibit the activity of NK cells. These results that KLRG1 recognizes the homodimeric interface of E-cadherin, that KLRG1 only binds to the monomeric form of E-cadherin, with an exposed N-terminal region, to immune such as NK cell cytotoxicity. In normal epithelial two E-cadherin molecules with other to form homodimeric junctions, as and thus they are not to NK cells or T cells However, E-cadherin may be exposed on the surfaces of disrupted or infected epithelial cells. In NK cells and T cells can E-cadherin by KLRG1, but this recognition in a Here, we that KLRG1 recognizes the N-terminal homodimer interface of E-cadherin and thus can only to the monomeric form to inhibit cytotoxicity. This monomeric form is to be expressed on epithelial Therefore, NK cells and T cells can mediate inhibitory responses KLRG1 binding to only monomeric E-cadherin. The interaction is and for the excess functional responses of NK cells as as of the SLECs This function is to that of inhibitory such as The receptor also recognizes E-cadherin K.L. Nature. PubMed Scopus Google Scholar). The is found on it their adhesion to epithelial cells and their function W.W. J.M. Curr. Opin. Cell Biol. 2000; PubMed Scopus Google Scholar). The recognizes the and its at the of E-cadherin domain 1 W.W. J.M. Curr. Opin. Cell Biol. 2000; PubMed Scopus Google Scholar), to the KLRG1 binding KLRG1 may with Although the expression of KLRG1 in not been KLRG1 is expressed with it may inhibit excess immune responses both by transducing inhibitory signals and by for can to both monomeric and homodimeric E-cadherin, KLRG1 binds only monomeric E-cadherin. This functional may have a potential to M. J. Exp. Med. 2006; 203: PubMed Scopus Google Scholar) as as NK and T cell of cancer cells express E-cadherin. of the E-cadherin is induced by the of or these result in the of domain 2 or domain 3 of E-cadherin and are to KLRG1 binding S. C. Schweier O. S. Becker K.F. Pircher H. J. Immunol. 2007; PubMed Scopus Google Scholar). However, suggest that the KLRG1 binding site is in the N-terminal region, from domains 2 and these may the of the N-terminal region that is for KLRG1 A of the structural of the E-cadherin and KLRG1 binding The or of E-cadherin in some cancer cells the of cell adhesion and the of tumor Such cells may be to NK cells and T cells, because of the of inhibitory signals. On the other hand, some may the interaction to their Such tumor cells might E-cadherin to and potential but E-cadherin to and immune by NK cells and T cells M. J. Exp. Med. 2006; 203: PubMed Scopus Google Scholar, S. C. Schweier O. S. Becker K.F. Pircher H. J. Immunol. 2007; PubMed Scopus Google Scholar, M. Curr. Opin. Cell Biol. PubMed Scopus Google Scholar, U. G. Rev. 2004; PubMed Scopus Google Scholar). Therefore, the development of of recognition is important for these cancer cells. results that KLRG1 recognizes the N-terminal of monomeric E-cadherin domain which are in the type I In KLRG1 can also to the other type I and and (5Ito M. Maruyama T. Saito N. Koganei S. Yamamoto K. Matsumoto N. J. Exp. Med. 2006; 203: 289-295Crossref PubMed Scopus (177) Google Scholar), that the N-terminal are a major for the KLRG1 Therefore, the N-terminal region may be a for of the This that KLRG1 recognizes the N-terminal region of E-cadherin, to be critical for homophilic adhesion. Therefore, we that KLRG1 cannot to the homodimeric form of E-cadherin but rather binds to the monomeric The monomeric form of E-cadherin is exposed on the in such as epithelial these it may as a for KLRG1 recognition to mediate inhibitory the activation threshold of NK cells and T cells and preventing immune response.

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