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• W2087433576 abstract "In this issue of Immunity, Voigt et al., 2007Voigt S. Mesci A. Ettinger J. Fine J.H. Chen P. Chou W. Carlyle J.R. Immunity. 2007; 26 (this issue): 617-627Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar and Lu et al., 2007Lu L. Ikizawa K. Hu D. Werneck M.B.F. Wucherpfennig K.W. Cantor H. Immunity. 2007; 26 (this issue): 593-604Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar extend the understanding of the consequences of missing-self recognition in immune evasion and immune cell regulation via NKRP-1 and CD94-NKG2A inhibitory receptors, respectively. In this issue of Immunity, Voigt et al., 2007Voigt S. Mesci A. Ettinger J. Fine J.H. Chen P. Chou W. Carlyle J.R. Immunity. 2007; 26 (this issue): 617-627Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar and Lu et al., 2007Lu L. Ikizawa K. Hu D. Werneck M.B.F. Wucherpfennig K.W. Cantor H. Immunity. 2007; 26 (this issue): 593-604Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar extend the understanding of the consequences of missing-self recognition in immune evasion and immune cell regulation via NKRP-1 and CD94-NKG2A inhibitory receptors, respectively. Natural killer (NK) cells are lymphocytes of the innate immune system that are known for their role in the control of viral infections and tumor development. The dissection of NK-cell-recognition strategies has been pivotal for the emergence of the “dynamic equilibrium” concept. NK cells are equipped with a variety of activating and inhibitory receptors, the engagement of which regulates NK-cell activities. It is thus the integration of antagonistic pathways upon interaction with neighboring cells that dictates whether NK cells are activated or not. NK-cell-activating receptors include cytokine receptors, integrins, and receptors that detect the presence of infectious nonself ligands (e.g., via Ly49H in the mouse) or stress-induced self ligands (e.g., via NKG2D). The inhibitory receptors that have been most studied so far are major histocompatibility complex (MHC)-class-1-specific receptors. NK cells loose their inhibition when encountering MHC-class-I-deficient hematopoietic cells in several in vitro and in vivo models. As a consequence, NK cells have been identified as recognizing missing-self on hematopoietic cells (Ljunggren and Kärre, 1990Ljunggren H.-G. Kärre K. Immunol. Today. 1990; 11: 237-244Abstract Full Text PDF PubMed Scopus (391) Google Scholar). The MHC-class-I-specific inhibitory receptors include the killer-cell immunoglobulin-like receptors (KIR) in humans, the lectin-like Ly49 dimers in the mouse, and the lectin-like CD94-NKG2A heterodimers in both species. A conserved feature of these inhibitory receptors resides in the presence of one or two intracytoplasmic inhibitory signaling domains, the immunoreceptor tyrosine-based inhibition motifs (ITIMs). By interacting with MHC class I molecules that are constitutively expressed by most cells in steady-state conditions but may be lost upon stress, inhibitory MHC class I receptors provide a way for NK cells to ensure tolerance to self, while allowing toxicity toward stressed cells. Besides their role in the control of NK-cell effector function, MHC-class-I-specific inhibitory receptors have also been shown to contribute to NK-cell maturation. Indeed, the recognition of self MHC class I by inhibitory receptors during NK-cell development is required for the capacity of NK cells to subsequently recognize missing-self MHC class I (Anfossi et al., 2006Anfossi N. Andre P. Guia S. Falk C.S. Roetynck S. Stewart C.A. Breso V. Frassati C. Reviron D. Middleton D. et al.Immunity. 2006; 25: 331-342Abstract Full Text Full Text PDF PubMed Scopus (815) Google Scholar) (Figure 1). Other inhibitory cell-surface receptors have been described in a variety of cell types, such as the NKR-P1 molecules (encoded by Klrb1) in NK-cell and T cell subsets. Klrb1 genes belong to a multigenic and mutiallelic gene family in rodents, whereas only one human KLRB1 ortholog has been found (encoding NKR-P1A). The identification of osteoclast inhibitory lectin (Ocil; also called C type lectin-related b [Clr-b]) as a ligand for mouse NKR-P1B revealed several interesting features (Carlyle et al., 2004Carlyle J.R. Jamieson A.M. Gasser S. Clingan C.S. Arase H. Raulet D.H. Proc. Natl. Acad. Sci. USA. 2004; 101: 3527-3532Crossref PubMed Scopus (171) Google Scholar, Iizuka et al., 2003Iizuka K. Naidenko O.V. Plougastel B.F. Fremont D.H. Yokoyama W.M. Nat. Immunol. 2003; 4: 801-807Crossref PubMed Scopus (221) Google Scholar). First, the genes encoding NKR-P1 molecules and their Clr-b ligands are intermingled within the NK gene complex (NKC) in rodents and humans. Second, NKR-P1 molecules and their ligands are C type lectin homodimers. In this issue of Immunity, Voigt et al., 2007Voigt S. Mesci A. Ettinger J. Fine J.H. Chen P. Chou W. Carlyle J.R. Immunity. 2007; 26 (this issue): 617-627Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar identify RCTL, a lectin encoded by rat cytomegalovirus (RCMV), as a ligand for the rat inhibitory NKR-P1B. The first clue for these findings came from the homology between RCTL and mouse Clr-b family members. Remarkably, engagement of RCTL with NKR-P1B dampens NK-cell activation, providing a MHC-class-I-independent mechanism for RCMV to evade NK-cell control (Voigt et al., 2007Voigt S. Mesci A. Ettinger J. Fine J.H. Chen P. Chou W. Carlyle J.R. Immunity. 2007; 26 (this issue): 617-627Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). Previous results had suggested a role for viral MHC class I homologs in the subversion of inhibitory receptors, such as UL-18, a human CMV product that binds the inhibitory receptor LIR-1 (ILT-2, LILRB1) or m157, a product of mouse CMV that binds the inhibitory Ly49I receptor in 129/J mice. Although appealing, this hypothesis remained to be strengthened. The RCTL:NKR-P1B interaction thus now provides compelling evidence that inhibitory receptors can be hijacked by pathogens, leading to a downregulation of the immune response. Importantly, these results also highlight the role of NKR-P1B:Clr-b interactions in MHC-class-I-independent missing-self recognition. Clr-b was previously reported to be frequently downregulated on mouse tumor cells, hence participating in the sensitivity of tumor cells to NK-cell attack (Carlyle et al., 2004Carlyle J.R. Jamieson A.M. Gasser S. Clingan C.S. Arase H. Raulet D.H. Proc. Natl. Acad. Sci. USA. 2004; 101: 3527-3532Crossref PubMed Scopus (171) Google Scholar). Voigt et al., 2007Voigt S. Mesci A. Ettinger J. Fine J.H. Chen P. Chou W. Carlyle J.R. Immunity. 2007; 26 (this issue): 617-627Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar now show that Clr-b is downregulated upon RCMV infection and that RCMV fights back against this missing-self recognition by providing a decoy ligand for NKR-P1B. Indeed, infection with a virus carrying a RCTL deletion results in a reduced viral titer in susceptible rats. In addition, wild-type and RCTL-deficient viruses present equal virulence upon NK-cell depletion in vivo. Except for MHC-mismatched hematopoietic transplantations, there is still very little evidence for a biological function of missing-self recognition in vivo. The correlation between the downregulation of Clr-b expression on RCMV-infected cells and the control of RCTL-deficient RCMV infection by NK cells strongly supports the importance of MHC-class-I-independent missing-self (Clr-b) recognition by NK cells in the control of a viral infection in vivo. New results regarding the role of missing-self recognition are also reported in this issue of Immunity (Lu et al., 2007Lu L. Ikizawa K. Hu D. Werneck M.B.F. Wucherpfennig K.W. Cantor H. Immunity. 2007; 26 (this issue): 593-604Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar). Like their HLA-E orthologs in humans, Qa-1 are nonpolymorphic MHC class Ib molecules, which present a restricted set of peptides, including leader sequences of MHC class Ia molecules. Using Qa-1-deficient and Qa-1 knockin mutant mice, Lu et al., 2007Lu L. Ikizawa K. Hu D. Werneck M.B.F. Wucherpfennig K.W. Cantor H. Immunity. 2007; 26 (this issue): 593-604Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar now show that NK cells kill autologous activated CD4+ T cells unless the latter express surface peptide:Qa-1 complexes. The inhibitory CD94-NKG2A dimers expressed on NK cells interact with peptide:Qa-1 complexes expressed on activated CD4+ T cells and govern the perforin-dependent NK-cell cytotoxicity against CD4+ T cells (Lu et al., 2007Lu L. Ikizawa K. Hu D. Werneck M.B.F. Wucherpfennig K.W. Cantor H. Immunity. 2007; 26 (this issue): 593-604Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar). These data are consistent with other recent reports revealing NK cells as immune regulators. In particular, NK cells can recognize and eliminate activated macrophages (Nedvetzki et al., 2007Nedvetzki S. Sowinski S. Eagle R.A. Harris J. Vely F. Pende D. Trowsdale J. Vivier E. Gordon S. Davis D.M. Blood. 2007; 109: 3776-3785Crossref PubMed Scopus (189) Google Scholar). This quality control of macrophages by NK cells might participate to the onset and/or progression of various inflammatory disorders such as those involving hemophagocytic syndromes. In addition, activated NKG2A+ NK cells kill human immature dendritic cells (DCs), and the upregulation of HLA-E (concomitant to increased in MHC class Ia expression) is responsible for sparing mature DCs. This process may shape subsequent T cell responses, particularly in the lymph nodes, where NKG2A+ cells represent the majority of NK cells (Moretta et al., 2006Moretta L. Ferlazzo G. Bottino C. Vitale M. Pende D. Mingari M.C. Moretta A. Immunol. Rev. 2006; 214: 219-228Crossref PubMed Scopus (228) Google Scholar). In the same line, in bone-marrow-graft settings supplemented with alloreactive NK cells, a graft-versus-leukemia effect was observed, but also decrease of graft-versus-host disease as well as increased bone-marrow engraftment (Ruggeri et al., 2006Ruggeri L. Aversa F. Martelli M.F. Velardi A. Immunol. Rev. 2006; 214: 202-218Crossref PubMed Scopus (138) Google Scholar). Additional data in this setting suggest that alloreactive donor NKs contribute to the destruction of host DCs (diminishing GVHD) and other host immune cells (facilitating engraftment) (Ruggeri et al., 2006Ruggeri L. Aversa F. Martelli M.F. Velardi A. Immunol. Rev. 2006; 214: 202-218Crossref PubMed Scopus (138) Google Scholar). These data prompt further examination of the role of NK cells in the control of immune homeostasis and investigations into the kinetics of expression of ligands for both inhibitory and activating ligands on CD4+ T cells (and other hematopoietic cells) during immune response. Dampening of Qa-1 on activated CD4+ T cells in late phases of immune responses might induce NK-cell susceptibility and therefore participate in the contraction of immune responses. These newly discovered functions of NK cells have been hidden for decades by the dissection of NK-cell effector function against microbe-infected cells and tumors, and their relative importance must now be evaluated in parallel. Yet, the manipulation of NK-cell regulatory functions might already lead to important clinical promises. Along these lines, Lu et al., 2007Lu L. Ikizawa K. Hu D. Werneck M.B.F. Wucherpfennig K.W. Cantor H. Immunity. 2007; 26 (this issue): 593-604Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar show that the blocking of Qa-1 interaction with CD94-NKG2A (via a Qa-1 R27A point mutant that selectively prevents the interaction between peptide:Qa-1 complexes and CD94-NKG2A, or via injection of Qa-1 antibodies) in experimental autoimmune encephalomyelitis (EAE) settings inhibits the development of the disease. These data suggest that blocking of NKG2A:HLA-E interaction may represent novel therapeutic strategies to manipulate NK cells in patients with autoimmune syndromes. Interestingly, the blocking of NK-cell Ly49 inhibitory receptors has been previously proposed to increase NK-cell effector function against tumor cells in vivo in the mouse (Koh et al., 2001Koh C.Y. Blazar B.R. George T. Welniak L.A. Capitini C.M. Raziuddin A. Murphy W.J. Bennett M. Blood. 2001; 97: 3132-3137Crossref PubMed Scopus (125) Google Scholar), without adverse effect. Thus, distinct MHC-class-I-specific inhibitory receptors could be targeted in different indications: (1) the blocking of KIR inhibitory receptors for MHC class Ia to prevent tumor progression by increasing NK-cell activity against MHC class I+ tumors (a strategy currently in phase I clinical trials in human acute myeloid leukemia), and (2) the blocking of CD94-NK2A inhibitory receptors for MHC class Ib to prevent CD4+ T cell-dependent autoimmunity. Many issues remain to be addressed to firmly settle the rationale of these protocols, such as the expression profile of HLA-E in humans. Finally, it should be stressed that the blocking of Qa-1 interaction with CD94-NKG2A also leads to an inhibition of recall antigen-driven CD4+ T cell response. This potential NK-cell-mediated immunosuppressive effect might appear as a serious limitation in the therapeutic use of drugs that block the CD94-NKG2A inhibitory function in humans, such as NKG2A or HLA-E antibodies. In autoimmune diseases, it seems that NK cells have divergent effects. In EAE, NK cells appear to dampen the pathogenic process by removing activated T cells in established disease (Lu et al., 2007Lu L. Ikizawa K. Hu D. Werneck M.B.F. Wucherpfennig K.W. Cantor H. Immunity. 2007; 26 (this issue): 593-604Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar). However, NK-cell activation may favor inflammation and therefore promote the onset of experimental diabetes models (Ogasawara et al., 2004Ogasawara K. Hamerman J.A. Ehrlich L.R. Bour-Jordan H. Santamaria P. Bluestone J.A. Lanier L.L. Immunity. 2004; 20: 757-767Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar). Given that injections of blocking NKG2D antibodies have been proposed to cure autoimmune diabetes (Ogasawara et al., 2004Ogasawara K. Hamerman J.A. Ehrlich L.R. Bour-Jordan H. Santamaria P. Bluestone J.A. Lanier L.L. Immunity. 2004; 20: 757-767Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar), it is tempting to investigate further the role of NKG2D in EAE, and the regulatory function of CD94-NKG2A on NKG2D-dependent NK-cell effector function. NK cells have long been considered in the search for biological functions. The “dynamic equilibrium” model of NK-cell activation now prompts us to target activating and inhibitory NK-cell signals in various pathological conditions. The use of inhibitory receptors by viruses to evade NK-cell control might be considered as a “natural” proof of principle for the efficiency of some of these innovative therapeutic strategies. E.V. is a shareholder and consultant of Innate Pharma. F.R. is a shareholder and employee of Innate Pharma. Regulation of Activated CD4+ T Cells by NK Cells via the Qa-1–NKG2A Inhibitory PathwayLu et al.ImmunityMay 25, 2007In BriefThe ability of natural-killer cells to regulate adaptive immunity is not well understood. Here we define an interaction between the class Ib major histocompatibility complex (MHC) molecule Qa-1–Qdm on activated T cells responsible for adaptive immunity and CD94–NKG2A inhibitory receptors expressed by natural-killer cells by using Qa-1-deficient and Qa-1 knockin mice containing a point mutation that selectively abolishes Qa-1–Qdm binding to CD94–NKG2A receptors. The Qa-1–NKG2A interaction protected activated CD4+ T cells from lysis by a subset of NKG2A+ NK cells and was essential for T cell expansion and development of immunologic memory. Full-Text PDF Open ArchiveCytomegalovirus Evasion of Innate Immunity by Subversion of the NKR-P1B:Clr-b Missing-Self AxisVoigt et al.ImmunityMay 25, 2007In BriefCytomegaloviruses are known to encode several gene products that function to subvert MHC-dependent immune recognition. Here we characterize a rat cytomegalovirus (RCMV) C-type lectin-like (RCTL) gene product with homology to the Clr ligands for the NKR-P1 receptors. RCMV infection rapidly extinguished host Clr-b expression, thereby sensitizing infected cells to killing by natural killer (NK) cells. However, the RCTL protein functioned as a decoy ligand to protect infected cells from NK killing via direct interaction with the NKR-P1B inhibitory receptor. Full-Text PDF Open Archive" @default.
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• W2087433576 title "Good News, Bad News for Missing-Self Recognition by NK Cells: Autoimmune Control but Viral Evasion" @default.
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