Regulation of T‐cell immunity by leucocyte immunoglobulin‐like receptors: innate immune receptors for self on antigen‐presenting cells

Following recognition of microbial patterns, innate immune receptors provide a rapid innate response and trigger antigen‐presenting cell maturation to instruct adaptive immune responses. Here we discuss a family of innate immune receptors for self – the leucocyte immunoglobulin‐like receptors (LILRs). These LILRs exert powerful inhibitory effects on antigen‐presenting cell phenotype and subsequent T‐cell responses, and may act to constrain the effects of Toll‐like receptor signalling. Despite their broad ligand specificity, differing affinities of LILRs for individual complexes of peptide–major histocompatiblity complex can determine the nature of their effect on downstream immune responses. Expression and function of LILRs may be skewed in certain conditions such as cancer or human immunodeficiency virus infection, particularly by ectopic expression of human leucocyte antigen‐G, a high‐affinity LILR ligand. We discuss the relevance of LILR‐mediated immune regulation across a range of scenarios from autoimmunity to transplant medicine, infection and cancer.

[1]  M. Colonna,et al.  Tolerization of dendritic cells by TS cells: the crucial role of inhibitory receptors ILT3 and ILT4 , 2002, Nature Immunology.

[2]  S. Goerdt,et al.  A gene signature of inhibitory MHC receptors identifies a BDCA3+ subset of IL‐10‐induced dendritic cells with reduced allostimulatory capacity in vitro , 2004, European journal of immunology.

[3]  J. Dausset,et al.  Modulation of dendritic cell differentiation by HLA-G and ILT4 requires the IL-6—STAT3 signaling pathway , 2008, Proceedings of the National Academy of Sciences.

[4]  Michael J. Wilson,et al.  Arrangement of the ILT gene cluster: a common null allele of the ILT6 gene results from a 6.7‐kbp deletion , 2000, European journal of immunology.

[5]  R. Apps,et al.  A critical look at HLA-G. , 2008, Trends in immunology.

[6]  D. Mancini,et al.  High expression of ILT3 and ILT4 is a general feature of tolerogenic dendritic cells. , 2003, Transplant immunology.

[7]  V. D’Agati,et al.  Soluble Ig-Like Transcript 3 Inhibits Tumor Allograft Rejection in Humanized SCID Mice and T Cell Responses in Cancer Patients1 , 2007, The Journal of Immunology.

[8]  Wei Zhang,et al.  Mechanisms of prolongation of allograft survival by HLA-G/ILT4-modified dendritic cells. , 2007, Human immunology.

[9]  M. Weller,et al.  Expression of the immune-tolerogenic major histocompatibility molecule HLA-G in multiple sclerosis: implications for CNS immunity. , 2005, Brain : a journal of neurology.

[10]  J. Dausset,et al.  Monocytes and T lymphocytes in HIV-1-positive patients express HLA-G molecule , 2002, AIDS.

[11]  H. Ljunggren,et al.  Human cytomegalovirus‐derived protein UL18 alters the phenotype and function of monocyte‐derived dendritic cells , 2008, Journal of leukocyte biology.

[12]  R. Dummer,et al.  Primary cutaneous CD8+ and CD56+ T-cell lymphomas express HLA-G and killer-cell inhibitory ligand, ILT2. , 2004, Blood.

[13]  M. Bonneville,et al.  Coordinated Expression of Ig-Like Inhibitory MHC Class I Receptors and Acquisition of Cytotoxic Function in Human CD8+ T Cells1 , 2004, Journal of Immunology.

[14]  Wei Cao,et al.  Plasmacytoid dendritic cell-specific receptor ILT7-Fc epsilonRI gamma inhibits Toll-like receptor-induced interferon production , 2006 .

[15]  Wei Zhang,et al.  Human Inhibitory Receptor Immunoglobulin-Like Transcript 2 Amplifies CD11b+Gr1+ Myeloid-Derived Suppressor Cells That Promote Long-Term Survival of Allografts , 2008, Transplantation.

[16]  Kouhei Tsumoto,et al.  Efficient Leukocyte Ig-like Receptor Signaling and Crystal Structure of Disulfide-linked HLA-G Dimer* , 2006, Journal of Biological Chemistry.

[17]  S. Kim-Schulze,et al.  Recombinant Ig-Like Transcript 3-Fc Modulates T Cell Responses via Induction of Th Anergy and Differentiation of CD8+ T Suppressor Cells1 , 2006, The Journal of Immunology.

[18]  J. S. Hunt,et al.  Synthesis of β2‐microglobulin‐free, disulphide‐linked HLA‐G5 homodimers in human placental villous cytotrophoblast cells , 2007, Immunology.

[19]  Wei Cao,et al.  Plasmacytoid dendritic cell–specific receptor ILT7–FcɛRIγ inhibits Toll-like receptor–induced interferon production , 2006, The Journal of experimental medicine.

[20]  R. Cortesini,et al.  ILT3+ ILT4+ Tolerogenic Endothelial Cells in Transplantation , 2006, Transplantation.

[21]  G. Aversa,et al.  Interleukin 10 regulates cell surface and soluble LIR‐2 (CD85d) expression on dendritic cells resulting in T cell hyporesponsiveness in vitro , 2004, European journal of immunology.

[22]  Wei Zhang,et al.  Tolerization of dendritic cells by HLA‐G , 2005, European journal of immunology.

[23]  M. Colonna,et al.  Nonleukoreduced red blood cell transfusion induces a sustained inhibition of neutrophil chemotaxis by stimulating in vivo production of transforming growth factor‐β1 by neutrophils: role of the immunoglobulinlike transcript 1, sFasL, and sHLA‐I , 2007, Transfusion.

[24]  P. Berloco,et al.  Detection of T suppressor cells in patients with organ allografts. , 2001, Human immunology.

[25]  Kouhei Tsumoto,et al.  Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[26]  J. Arm Generation of cytokines through the leucocyte immunoglobulin‐like receptors , 2004 .

[27]  T. Bellón,et al.  Amoxicillin conjugates to HLA class I molecules and interferes with signalling through the ILT2/LIR‐1/CD85j inhibitory receptor , 2007, Allergy.

[28]  D. Scott‐Algara,et al.  The CD85j+ NK Cell Subset Potently Controls HIV-1 Replication in Autologous Dendritic Cells , 2008, PloS one.

[29]  N. Rouas-Freiss,et al.  Evidence to Support the Role of HLA-G5 in Allograft Acceptance through Induction of Immunosuppressive/ Regulatory T Cells1 , 2006, The Journal of Immunology.

[30]  G. Leclercq,et al.  Interactions of Ly49 Family Receptors with MHC Class I Ligands in trans and cis1 , 2007, The Journal of Immunology.

[31]  D. Mancini,et al.  Alloantigen specific CD8+CD28- FOXP3+ T suppressor cells induce ILT3+ ILT4+ tolerogenic endothelial cells, inhibiting alloreactivity. , 2004, International immunology.

[32]  M. Colonna,et al.  Cloning of novel immunoglobulin superfamily receptors expressed on human myeloid and lymphoid cells: Structural evidence for new stimulatory and inhibitory pathways , 1997, European journal of immunology.

[33]  M. Derrien,et al.  The short cytoplasmic tail of HLA-G determines its resistance to HIV-1 Nef-mediated cell surface downregulation. , 2004, Human immunology.

[34]  S. Agrawal,et al.  The role of human leukocyte antigen E and G in HIV infection. , 2007, AIDS.

[35]  Todd M. Allen,et al.  A viral CTL escape mutation leading to immunoglobulin-like transcript 4–mediated functional inhibition of myelomonocytic cells , 2007, The Journal of experimental medicine.

[36]  R. Cortesini,et al.  Central role of ILT3 in the T suppressor cell cascade. , 2007, Cellular immunology.

[37]  P. Vermersch,et al.  Association of multiple sclerosis with ILT6 deficiency , 2005, Genes and Immunity.

[38]  R. González-Amaro,et al.  Analysis of expression and function of the inhibitory receptor ILT2 (CD85j/LILRB1/LIR-1) in peripheral blood mononuclear cells from patients with systemic lupus erythematosus (SLE). , 2007, Journal of autoimmunity.

[39]  M. Kubin,et al.  A novel immunoglobulin superfamily receptor for cellular and viral MHC class I molecules. , 1997, Immunity.

[40]  S. Kim-Schulze,et al.  Role of regulatory and suppressor T-cells in the induction of ILT3+ ILT4+ tolerogenic endothelial cells in organ allografts. , 2004, Transplant immunology.

[41]  J. Strominger,et al.  Disulfide bond-mediated dimerization of HLA-G on the cell surface , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[42]  F. Mulcahy,et al.  Natural Killer cells from long-term non-progressor HIV patients are characterized by altered phenotype and function. , 2007, Clinical immunology.

[43]  Kouhei Tsumoto,et al.  Structural basis for recognition of the nonclassical MHC molecule HLA-G by the leukocyte Ig-like receptor B2 (LILRB2/LIR2/ILT4/CD85d) , 2006, Proceedings of the National Academy of Sciences.

[44]  Masahiro Yamamura,et al.  Use of Genetic Profiling in Leprosy to Discriminate Clinical Forms of the Disease , 2003, Science.

[45]  V. Guiard,et al.  © 1999 The Japanese Society for Immunology IL-10 selectively induces HLA-G expression in human trophoblasts and monocytes , 2022 .

[46]  Philippe Moreau,et al.  HLA-G: from biology to clinical benefits. , 2008, Trends in immunology.

[47]  E. Carosella,et al.  HLA‐G up‐regulates ILT2, ILT3, ILT4, and KIR2DL4 in antigen presenting cells, NK cells, and T cells , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[48]  G. Cheng,et al.  LILRA2 Activation Inhibits Dendritic Cell Differentiation and Antigen Presentation to T Cells1 , 2007, The Journal of Immunology.

[49]  G. Screaton,et al.  Ig-Like Transcript 4 Inhibits Lipid Antigen Presentation through Direct CD1d Interaction1 , 2009, The Journal of Immunology.

[50]  J. Dausset,et al.  HLA-G expression in melanoma: a way for tumor cells to escape from immunosurveillance. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[51]  J. Trowsdale,et al.  The inhibitory receptor LILRB1 modulates the differentiation and regulatory potential of human dendritic cells. , 2008, Blood.

[52]  G. Trinchieri,et al.  CD85j (Leukocyte Ig-Like Receptor-1/Ig-Like Transcript 2) Inhibits Human Osteoclast-Associated Receptor-Mediated Activation of Human Dendritic Cells1 , 2005, The Journal of Immunology.

[53]  M. Colonna,et al.  Human myeloid cells express an activating ILT receptor (ILT1) that associates with Fc receptor gamma-chain. , 1999, Journal of immunology.

[54]  V. D’Agati,et al.  Immunoglobulin-Like Transcript 3-Fc Suppresses T-Cell Responses to Allogeneic Human Islet Transplants in hu-NOD/SCID Mice , 2008, Diabetes.

[55]  N. Rouas-Freiss,et al.  NK resistance of tumor cells from multiple myeloma and chronic lymphocytic leukemia patients: implication of HLA-G , 2008, Leukemia.

[56]  M. Kubin,et al.  LIR9, an immunoglobulin-superfamily-activating receptor, is expressed as a transmembrane and as a secreted molecule. , 2003, Blood.

[57]  A. Nakamura,et al.  Cis binding between inhibitory receptors and MHC class I can regulate mast cell activation , 2007, The Journal of experimental medicine.

[58]  C. Reis e Sousa,et al.  Toll-like receptors and dendritic cells: for whom the bug tolls. , 2004, Seminars in immunology.

[59]  N. Rouas-Freiss,et al.  Beyond the increasing complexity of the immunomodulatory HLA-G molecule. , 2008, Blood.

[60]  N. Rouas-Freiss,et al.  Soluble HLA-G and HLA-G1 expressing antigen-presenting cells inhibit T-cell alloproliferation through ILT-2/ILT-4/FasL-mediated pathways. , 2007, Human immunology.

[61]  A. McMichael,et al.  Cell-surface expression and immune receptor recognition of HLA-B27 homodimers. , 2002, Arthritis and rheumatism.

[62]  M. Zenke,et al.  Immunoglobulin-like transcripts ILT2, ILT3 and ILT7 are expressed by human dendritic cells and down-regulated following activation. , 2004, Gene.

[63]  C. Gleissner,et al.  IL‐10 inhibits endothelium‐dependent T cell costimulation by up‐regulation of ILT3/4 in human vascular endothelial cells , 2007, European journal of immunology.

[64]  S. Beck,et al.  Plasticity in the organization and sequences of human KIR/ILT gene families. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[65]  D. Cosman,et al.  Activation of human eosinophils through leukocyte immunoglobulin-like receptor 7 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[66]  U. Švajger,et al.  Niflumic acid renders dendritic cells tolerogenic and up-regulates inhibitory molecules ILT3 and ILT4. , 2008, International immunopharmacology.

[67]  Michael J. Wilson,et al.  Killer Cell Ig-Like Receptor and Leukocyte Ig-Like Receptor Transgenic Mice Exhibit Tissue- and Cell-Specific Transgene Expression 1 , 2003, The Journal of Immunology.

[68]  G. Vlad,et al.  Regulatory CD8+CD28- T cells in heart transplant recipients. , 2003, Human immunology.

[69]  G. Bhagat,et al.  Expression of inhibitory receptor ILT3 on neoplastic B cells is associated with lymphoid tissue involvement in chronic lymphocytic leukemia , 2007, Cytometry. Part B, Clinical cytometry.

[70]  Giuseppe Penna,et al.  Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4+Foxp3+ regulatory T cells by 1,25-dihydroxyvitamin D3. , 2005, Blood.

[71]  N. Rouas-Freiss,et al.  Expression of tolerogenic HLA-G molecules in cancer prevents antitumor responses. , 2007, Seminars in cancer biology.

[72]  P. Bjorkman,et al.  Crystal structure of HLA-A2 bound to LIR-1, a host and viral major histocompatibility complex receptor , 2003, Nature Immunology.

[73]  B. Mordmüller,et al.  Increase in annexin V-positive B cells expressing LILRB1/ILT2/CD85j in malaria. , 2006, European cytokine network.

[74]  D. Jarrossay,et al.  Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon , 1999, Nature Medicine.

[75]  K. Austen,et al.  Leukocyte immunoglobulin-like receptors: novel innate receptors for human basophil activation and inhibition. , 2004, Blood.

[76]  M. Colonna,et al.  Cutting Edge: Human Myeloid Cells Express an Activating ILT Receptor (ILT1) That Associates with Fc Receptor γ-Chain , 1999, The Journal of Immunology.

[77]  P. Parham,et al.  Conserved organization of the ILT/LIR gene family within the polymorphic human leukocyte receptor complex , 2001, Immunogenetics.

[78]  A. McMichael,et al.  Expression of leukocyte immunoglobulin-like receptors and natural killer receptors on virus-specific CD8+ T cells during the evolution of Epstein-Barr virus-specific immune responses in vivo. , 2005, Viral immunology.

[79]  J. S. Hunt,et al.  Novel HLA-G-binding leukocyte immunoglobulin-like receptor (LILR) expression patterns in human placentas and umbilical cords. , 2008, Placenta.

[80]  E. Carosella,et al.  Soluble HLA‐G Expression and Renal Graft Acceptance , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[81]  R. Lechler,et al.  Aspirin‐Treated Human DCs Up‐Regulate ILT‐3 and Induce Hyporesponsiveness and Regulatory Activity in Responder T Cells , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[82]  F. Gros,et al.  Elevated levels of soluble non‐classical major histocompatibility class I molecule human leucocyte antigen (HLA)‐G in the blood of HIV‐infected patients with or without visceral leishmaniasis , 2006, Clinical and experimental immunology.

[83]  S. Kim-Schulze,et al.  Molecular characterization of allospecific T suppressor and tolerogenic dendritic cells: review. , 2005, International immunopharmacology.

[84]  P. Gao,et al.  Expression of Ig-like transcript 4 inhibitory receptor in human non-small cell lung cancer. , 2008, Chest.

[85]  K. Arai,et al.  SAGE library screening reveals ILT7 as a specific plasmacytoid dendritic cell marker that regulates type I IFN production. , 2008, International immunology.

[86]  A. Makrigiannis,et al.  Positive regulation of plasmacytoid dendritic cell function via Ly49Q recognition of class I MHC , 2008, The Journal of experimental medicine.

[87]  M. Claesson,et al.  Induction of regulatory dendritic cells by dexamethasone and 1alpha,25-Dihydroxyvitamin D(3). , 2004, Immunology letters.

[88]  L. O’Neill When signaling pathways collide: positive and negative regulation of toll-like receptor signal transduction. , 2008, Immunity.

[89]  R. González-Amaro,et al.  Phenotypic Analysis of IL‐10‐treated, Monocyte‐derived Dendritic Cells in Patients with Systemic Lupus Erythematosus , 2006, Scandinavian journal of immunology.

[90]  W. Heath,et al.  Immunity or tolerance? That is the question for dendritic cells , 2001, Nature Immunology.

[91]  J. Lieberman,et al.  Increased expression of the natural killer cell inhibitory receptor CD85j/ILT2 on antigen‐specific effector CD8 T cells and its impact on CD8 T‐cell function , 2004, Immunology.

[92]  S. Olofsson,et al.  LIR-1 expression on lymphocytes, and cytomegalovirus disease in lung-transplant recipients , 2003, The Lancet.

[93]  Michael J. Wilson,et al.  Cutting Edge: Leukocyte Receptor Complex-Encoded Immunomodulatory Receptors Show Differing Specificity for Alternative HLA-B27 Structures1 , 2001, The Journal of Immunology.

[94]  C. Geczy,et al.  Down-regulation of leucocyte immunoglobulin-like receptor expression in the synovium of rheumatoid arthritis patients after treatment with disease-modifying anti-rheumatic drugs. , 2007, Rheumatology.

[95]  R. Schmidt,et al.  Immunoglobulin‐like Transcripts as Risk Genes for Autoimmunity , 2007, Annals of the New York Academy of Sciences.

[96]  M. Claesson,et al.  Induction of regulatory dendritic cells by dexamethasone and 1α,25-Dihydroxyvitamin D3 , 2004 .

[97]  G. Vlad,et al.  Interleukin-10 induces the upregulation of the inhibitory receptor ILT4 in monocytes from HIV positive individuals. , 2003, Human immunology.