Inhibitory and activating receptors of the innate immune system





    A number of surface receptors playing an inhibitory role have been identified in different leucocyte lineages; some belong to the Immunoglobulin superfamily (Ig-SF) whereas others are lectin-like molecules. Several of these receptors have been extensively characterized in Natural Killer cells and T lymphocytes. The inhibitory mechanism involves cytoplasmic recruitment of SH2 domain-containing tyrosine phosphatases. These receptor families often include other members with a triggering function. Some receptors recognize well-defined molecules (MHC class I molecules, IgG, sialic acid); yet, the nature of ligands remains largely unknown.

Analysis of the structure, genetic polymorphism, distribution and function of these receptor-ligand systems is revealing novel aspects on the regulation of the immune response, and may provide clues to understand the pathophysiology of immune disorders.

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  •    Molecular characterization of leukocyte inhibitory receptors and their activating homologues.

  •    Study of NK cell-associated receptors in the immune response to human cytomegalovirus (HCMV) infection.


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    M. López-Botet, was formerly based at the Hospital Universitario de la Princesa (Universidad Autónoma of Madrid) from 1985 until 1999. Main contributions have been the characterization of CD94/NKG2 lectin-like Natural Killer (NK) receptors specific for HLA-E, and of the ILT2 (LIR1, CD85j) leukocyte inhibitory receptor for HLA class I molecules. A number of fruitful collaborations have been established with other laboratories.
Current external collaborations:

  •    Dr. Ana Angulo. Virology. IDIBAPS. Barcelona.

  •    Dr. Carlos Vilches. Dpt. of Immunology. Hospital Universitario Puerta de Hierro. Madrid.

  •    Dr. Hartmut Hengel. Institute for Virology. University Düsseldorf.

 Monoclonal antibodies generated by the lab have been distributed to other laboratories and licensed for commercialization. The PI has published 123 articles in international journals (PubMed, ISI Web of Science). The following list includes a selection of relevant and/or recent publications.
  • Carretero M., Cantoni C., Bellón T., Bottino C., Biassoni R., Rodríguez A., Pérez-Villar J.J., Moretta A., Moretta L., López-Botet M. (1997). The CD94 and NKG2-A C-type lectins covalently assemble to form an inhibitory receptor for HLA class I molecules. Eur. J. Immunol. 27:563.
  • Colonna M., Navarro F., Bellón T., Llano M., García P., Samaridis J., Angman L., Cella M., López-Botet M., (1997) A common inhibitory receptor for Major Histocompatibility Complex Class I molecules on human lymphoid and myelomonocytic cells. J. Exp. Med. 186:1809.
  • Carretero, M., Palmieri G., Llano M., Tullio V., Santoni A., Geraghty D.E., and López-Botet M. (1998). Specific engagement of the CD94/NKG2A killer inhibitory receptor by the HLA-E class Ib molecule induces SHP-1 phosphatase recruitment to tyrosine-phosphorylated NKG2A: evidence for receptor function in heterologous transfectants. Eur.J.Immunol. 28:1280.
  • Lee, N., Llano M., Carretero M., Ishitani A., Navarro F., López-Botet M., and D.E. Geraghty. (1998). HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proc.Natl.Acad.Sci.U.S.A. 95:5199.
  • Llano, M., Lee N., Navarro F., García P., Albar J.P., Geraghty D.E., and López-Botet M. (1998). HLA-E-bound peptides influence recognition by inhibitory and triggering CD94/NKG2 receptors: preferential response to an HLA-G-derived nonamer. Eur J Immunol 28:2854.
  • Navarro, F., Llano M., Bellón T., Colonna M., Geraghty D.E., and López-Botet M.(1999). The ILT2 (LIR-1) and CD94/NKG2A NK cell receptors respectively recognize HLA-G1 and HLA-E molecules co-expressed on target cells. Eur. J.Immunol. 29:277.
  • López-Botet M., and Bellón T. (1999). NK cell activation and inhibition by receptors for MHC class I. Curr. Opin. Immunol. 11:301
  • Valés-Gómez, M., H.T. Reyburn, R.A. Erskine, M. López-Botet, and J.L. Strominger. 1999. Kinetics and peptide dependency of the binding of the inhibitory NK receptor CD94/NKG2-A and the activating receptor CD94/NKG2-C to HLA-E. EMBO J. 18:4250
  • Carretero, M, Llano, M, Navarro, F, Bellon, T, Lopez-Botet, M. 2000. Mitogen-activated protein kinase activity is involved in effector functions triggered by the CD94/NKG2-C NK receptor specific for HLA-E. Eur J Immunol; 30:2842
  • Lopez-Botet M., Llano M., and Ortega M. (2001) Human cytomegalovirus and natural killer-mediated surveillance of HLA class I expression: a paradigm of host-pathogen adaptation. Immunol.Rev. 181: 193-202.
  • García P., Llano M., Heredia A.B., Willberg C., Caparrós E., Aparicio P., Braud, V.M., and López-Botet M. (2002) Human T cell receptor-mediated recognition of HLA-E. Eur.J. Immunol. 32:936-944
  • Bellón T., Kitzig F., Sayós J., and López-Botet M. (2002) Mutational analysis of Immunoreceptor Tyrosine-based Inhibition Motifs of the Ig-like transcript 2 (CD85j) leukocyte receptor. J. Immunol. 168:3351-3359
  • Llano M., Gumá M., Ortega M., Angulo A., López-Botet M.. (2003). Differential effects of US2, US6 and US11 human cytomegalovirus proteins on HLA class Ia and HLA-E expression: impact on target susceptibility to NK cell subsets. Eur J Immunol. 33:2744-2754.
  • López-Botet M., Angulo A., Gumá M. (2004). NK cell receptors for MHC class I and related molecules in cytomegalovirus infection. Tissue Antigens 63: 195-203.
  • García P, De Heredia AB, Bellón T, Carpio E, Llano M, Caparrós E, Aparicio P, López-Botet M. (2004). Signalling via CD70, a member of the TNF family, regulates T cell functions. J. Leukoc. Biol. 76:263-70.
  • Aguilar, H., Alvarez-Errico, D., García-Montero, A.C., Orfao, A., Sayós, J., and López-Botet, M. (2004). Molecular characterization of a novel immune receptor restricted to the monocytic lineage. J.Immunol. 173: 6703-6711
  • Alvarez-Errico, D., Aguilar, H., Kitzig, F., Brckalo, T., Sayós, J., and López-Botet, M. (2004). IREM-1 is a novel inhibitory receptor expressed by myeloid cells. Eur.J.Immunol. 34: 3690-3701.
  • Sayós, J., Martinez-Barriocanal, A., Kitzig, F., Bellón, T., and López-Botet, M. (2004). Recruitment of C-terminal Src kinase by the leukocyte inhibitory receptor CD85j. Biochem.Biophys.Res.Commun. 324: 640-647.
  • Gumá, M., Angulo, A., Vilches, C., Gómez-Lozano, N., Malats, N., and López-Botet, M. (2004). Imprint of human cytomegalovirus infection on the NK cell receptor repertoire. Blood 2004. 104: 3664-3671.
  • Gumá M., Busch L.K., Salazar-Fontana L.I., Bellosillo B., Morte C., García P., López-Botet M. (2005) The CD94/NKG2C killer lectin-like receptor constitutes an alternative activation pathway for a subset of CD8(+) T cells. Eur.J.Immunol. 35: 2071-2080.
  • Gumá, M., Angulo A., and López-Botet M.(2006) NK cell receptors involved in the response to human cytomegalovirus infection. Curr. Top. Microbiol. Immunol. 298:207-223
  • Gumá M,Budt M,Sáez A,Brckalo T,Hengel H,Angulo A,López-Botet M.(2006) Expansion of CD94/NKG2C+ NK cells in response to human cytomegalovirus-infected fibroblasts. Blood. 107:3624-3631
  • Gumá M,Cabrera C,Erkizia I,Bofill M,Clotet B,Ruiz L,López-Botet M (2006) Human cytomegalovirus infection is associated with increased proportions of NK cells that express the CD94/NKG2C receptor in aviremic HIV-1 infected patients.J.Inf.Dis.194:38-41
  • Sáez-Borderías A,Gumá M,Angulo A,Bellosillo B,Pende D,López-Botet M.(2006) Expression and function of NKG2D in CD4+ T cells specific for human cytomegalovirus. Eur. J. Immunol. 36:3198-206
  • Alvarez-Errico D,Sayós J,López-Botet M.(2007) The IREM-1 (CD300f) inhibitory receptor associates with the p85 subunit of phosphoinositide 3-kinase. J. Immunol. 178:808-16
  • Estefania E,Flores R,Gomez-Lozano N,Aguilar H,Lopez-Botet M,Vilches C.(2007) Human KIR2DL5 is an inhibitory receptor expressed on the surface of NK and T lymphocyte subsets. J. Immunol.178:4402-10

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  • Characterization of the NK cell receptor (NKR) repertoire involved in the response to human cytomegalovirus (HCMV). Ministry of Education and Science (SAF 2004/07632) (2005-2007).

  • Natural Killer cell-mediated anti-viral and anti tumour defence and therapy. Marie Curie Research Training Network. University Pompeu Fabra (MRTN-CT-2005-019248) (2006-2008).

  • Analysis of the involvement of NK cell receptor in the immune response to human cytomegalovirus. Ministry of Education and Science. University Pompeu Fabra (SAF 2007/61814) (2007-2009).

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    Ph.D. Thesis
       
  • Ph.D. Thesis Director (17 accomplished)
       Mónica Gumá Uriel. University Pompeu Fabra. 2005.(codirector A. Angulo)
       Damiana Alvarez Errico. University Pompeu Fabra. 2006.(codirector J. Sayós)
       Helena Aguilar Calafell. University Pompeu Fabra. 2006.(codirector J. Sayós)



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