Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Cis interactions of immunoreceptors with MHC and non-MHC ligands

Nature Reviews Immunology volume 8, pages 269–278 (2008)Cite this article

Key Points

  • Cell-surface receptors interact with ligands expressed by other cells to allow cell-to-cell communication (trans interactions). In addition, a small number of cell-surface receptors can engage the equivalent ligand expressed by the same cell (cis interaction).

  • Immunoreceptors that can bind MHC class I ligand in cis and in trans belong to two structurally distinct receptor families — that is, the C-type lectin-like Ly49 receptors and the immunoglobulin-like receptors LILRB1 (leukocyte immunoglobulin-like receptor B1) and PIRB (paired immunoglobulin-like receptor B). In addition, immunoglobulin-like Siglecs bind sialic-acid-modified glycoproteins in cis.

  • Structural considerations suggest that ligand binding in cis versus trans depends on unusually long stalk regions (Ly49 receptors) or on very flexible (or multiple) interdomain hinges (LILRB1 and PIRB).

  • Cis interactions are a feature of immunoreceptors that inhibit rather than activate cellular functions.

  • Cis interactions can increase or decrease the threshold at which cellular activation signalling translates into a biological response. It facilitates the activation of natural killer (NK) cells, as the number of inhibitory Ly49 receptors available to functionally interact with the MHC class I ligand in trans is reduced. By contrast, the PIRB–MHC class I interaction dampens mast-cell activation.

Abstract

The conventional wisdom is that cell-surface receptors interact with ligands expressed on other cells to mediate cell-to-cell communication (trans interactions). Unexpectedly, it has recently been found that two classes of receptors specific for MHC class I molecules not only interact with MHC class I molecules expressed on opposing cells, but also with those on the same cell. These cis interactions are a feature of immunoreceptors that inhibit, rather than activate, cellular functions. Here, we review situations in which cis interactions have been observed, the characteristics of receptors that bind in trans and cis, and the biological roles of cis recognition.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Structures of MHC class I receptors.
Figure 2: Hypothetical models for trans and cis interactions of Ly49 receptors and LILRs with MHC class I ligands.
Figure 3: Physiological role of cis and trans interactions of Ly49A, PIRB and CD22.

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. Zinkernagel, R. M. & Doherty, P. C. Restriction of in vitro T cell-mediated cytoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature 248, 701–702 (1974).

    Article  CAS  Google Scholar 

  2. Snell, G. D. The genetics of transplantation. J. Natl Cancer Inst. 14, 691–700 (1953).

    CAS  PubMed  Google Scholar 

  3. Cudkowicz, G. & Bennett, M. Peculiar immunobiology of bone marrow allografts. I. Graft rejection by irradiated responder mice. J. Exp. Med. 134, 83–102 (1971).

    Article  CAS  Google Scholar 

  4. Ljunggren, H. G. & Kärre, K. In search of the 'missing self': MHC molecules and NK cell recognition. Immunol. Today 11, 237–244 (1990).

    Article  CAS  Google Scholar 

  5. Yu, Y. Y. et al. The role of Ly49A and 5E6(Ly49C) molecules in hybrid resistance mediated by murine natural killer cells against normal T cell blasts. Immunity 4, 67–76 (1996).

    Article  CAS  Google Scholar 

  6. Karlhofer, F. M., Ribaudo, R. K. & Yokoyama, W. M. MHC class I alloantigen specificity of Ly-49+ IL-2-activated natural killer cells. Nature 358, 66–70 (1992).

    Article  CAS  Google Scholar 

  7. Smith, H. R. C., Karlhofer, F. M. & Yokoyama, W. M. Ly-49 multigene family expressed by IL-2-activated NK cells. J. Immunol. 153, 1068–1079 (1994).

    CAS  PubMed  Google Scholar 

  8. Moretta, A. et al. P58 molecules as putative receptors for major histocompatibility complex (MHC) class I molecules in human natural killer (NK) cells. Anti-p58 antibodies reconstitute lysis of MHC class I-protected cells in NK clones displaying different specificities. J. Exp. Med. 178, 597–604 (1993).

    Article  CAS  Google Scholar 

  9. Colonna, M. & Samaridis, J. Cloning of immunoglobulin-superfamily members associated with HLA-C and HLA-B recognition by human natural killer cells. Science 268, 405–408 (1995).

    Article  CAS  Google Scholar 

  10. Wagtmann, N. et al. Molecular clones of the p58 natural killer cell receptor reveal Ig-related molecules with diversity in both the extra- and intra-cellular domains. Immunity 2, 439–449 (1995).

    Article  CAS  Google Scholar 

  11. Braud, V. M. et al. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391, 795–799 (1998).

    Article  CAS  Google Scholar 

  12. Vance, R. E., Kraft, J. R., Altman, J. D., Jensen, P. E. & Raulet, D. H. Mouse CD94/NKG2A is a natural killer cell receptor for the nonclassical major histocompatibility complex (MHC) class I molecule Qa-1b. J. Exp. Med. 188, 1841–1848 (1998).

    Article  CAS  Google Scholar 

  13. Colonna, M. et al. A common inhibitory receptor for major histocompatibility complex class I molecules on human lymphoid and myelomonocytic cells. J. Exp. Med. 186, 1809–1818 (1997).

    Article  CAS  Google Scholar 

  14. Kubagawa, H., Burrows, P. D. & Cooper, M. D. A novel pair of immunoglobulin-like receptors expressed by B cells and myeloid cells. Proc. Natl Acad. Sci. USA 94, 5261–5266 (1997).

    Article  CAS  Google Scholar 

  15. Doucey, M. A. et al. Cis-association of Ly49A with MHC class I restricts natural killer cell inhibition. Nature Immunol. 5, 328–336 (2004). This report provides the first direct evidence that an MHC class I receptor (Ly49A) not only binds to a ligand on an opposing cell membrane but also interacts with a ligand expressed on the same membrane. Cis interaction is shown to inhibit inhibition, thereby facilitating NK-cell activation.

    Article  CAS  Google Scholar 

  16. Masuda, A., Nakamura, A., Maeda, T., Sakamoto, Y. & Takai, T. Cis binding between inhibitory receptors and MHC class I can regulate mast cell activation. J. Exp. Med. 204, 907–920 (2007). This paper demonstrates cis binding of MHC class I ligands by immunoglobulin-like LILRB1 and PIRB. In these cases, the cis interaction is thought to dampen mast-cell activation.

    Article  CAS  Google Scholar 

  17. Rudolph, M. G., Stanfield, R. L. & Wilson, I. A. How TCRs bind MHCs, peptides, and coreceptors. Annu. Rev. Immunol. 24, 419–466 (2006).

    Article  CAS  Google Scholar 

  18. Bix, M. & Raulet, D. Inefficient positive selection of T cells directed by hematopoietic cells. Nature 359, 330–333 (1992).

    Article  CAS  Google Scholar 

  19. Schott, E., Bertho, N., Ge, Q., Maurice, M. M. & Ploegh, H. L. Class I negative CD8 T cells reveal the confounding role of peptide-transfer onto CD8 T cells stimulated with soluble H2-Kb molecules. Proc. Natl Acad. Sci. USA 99, 13735–13740 (2002).

    Article  CAS  Google Scholar 

  20. Anderson, S. K., Ortaldo, J. R. & McVicar, D. W. The ever-expanding Ly49 gene family: repertoire and signaling. Immunol. Rev. 181, 79–89 (2001).

    Article  CAS  Google Scholar 

  21. Hanke, T. et al. Direct assessment of MHC class I binding by seven Ly49 inhibitory NK cell receptors. Immunity 11, 67–77 (1999).

    Article  CAS  Google Scholar 

  22. Correa, I. & Raulet, D. H. Binding of diverse peptides to MHC class I molecules inhibits target cell lysis by activated natural killer cells. Immunity 2, 61–71 (1995).

    Article  CAS  Google Scholar 

  23. Franksson, L. et al. Peptide dependency and selectivity of the NK cell inhibitory receptor Ly-49C. Eur. J. Immunol. 29, 2748–2758 (1999).

    Article  CAS  Google Scholar 

  24. Hanke, T. & Raulet, D. H. Cumulative inhibition of NK cells and T cells resulting from engagement of multiple inhibitory Ly49 receptors. J. Immunol. 166, 3002–3007 (2001).

    Article  CAS  Google Scholar 

  25. Scarpellino, L. et al. Interactions of Ly49 family receptors with MHC class I ligands in trans and cis. J. Immunol. 178, 1277–1284 (2007).

    Article  CAS  Google Scholar 

  26. Dam, J. et al. Variable MHC class I engagement by Ly49 natural killer cell receptors demonstrated by the crystal structure of Ly49C bound to H-2Kb. Nature Immunol. 4, 1213–1222 (2003). The structures described in references 26, 27 and 32 reveal significant variability in Ly49-receptor dimerization and engagement of MHC class I ligands. The bivalent Ly49C–H2-Kb and monovalent Ly49A–H2-Dd complexes might represent trans and cis recognition, respectively.

    Article  CAS  Google Scholar 

  27. Tormo, J., Natarajan, K., Margulies, D. H. & Mariuzza, R. A. Crystal structure of a lectin-like natural killer cell receptor bound to its MHC class I ligand. Nature 402, 623–631 (1999).

    Article  CAS  Google Scholar 

  28. Deng, L. & Mariuzza, R. A. Structural basis for recognition of MHC and MHC-like ligands by natural killer cell receptors. Semin. Immunol. 18, 159–166 (2006).

    Article  CAS  Google Scholar 

  29. Gao, G. F. et al. Crystal structure of the complex between human CD8aa and HLA-A2. Nature 387, 630–634 (1997).

    Article  CAS  Google Scholar 

  30. Matsumoto, N., Mitsuki, M., Tajima, K., Yokoyama, W. M. & Yamamoto, K. The functional binding site for the C-type lectin-like natural killer cell receptor Ly49A spans three domains of its major histocompatibility complex class I ligand. J. Exp. Med. 193, 147–157 (2001).

    Article  CAS  Google Scholar 

  31. Wang, J. et al. Binding of the natural killer cell inhibitory receptor Ly49A to its major histocompatibility complex class I ligand. J. Biol. Chem. 277, 1433–1442 (2002).

    Article  CAS  Google Scholar 

  32. Dam, J. et al. Variable dimerization of the Ly49A natural killer cell receptor results in differential engagement of its MHC class I ligand. J. Mol. Biol. 362, 102–113 (2006).

    Article  CAS  Google Scholar 

  33. Zimmer, J., Ioannidis, V. & Held, W. H-2D ligand expression by Ly49A+ natural killer (NK) cells precludes ligand uptake from environmental cells: implications for NK cell function. J. Exp. Med. 194, 1531–1539 (2001).

    Article  CAS  Google Scholar 

  34. Back, J., Chalifour, A., Scarpellino, L. & Held, W. Stable masking by H-2Ddcis ligand limits Ly49A relocalization to the site of NK cell/target cell contact. Proc. Natl Acad. Sci. USA 104, 3978–3983 (2007). This paper shows that Ly49A remains stably associated with cis H2-Dd during NK-cell–target-cell interactions, thereby reducing trans H2-Dd-driven Ly49A recruitment to the NK-cell synapse.

    Article  CAS  Google Scholar 

  35. Andersson, K. E., Williams, G. S., Davis, D. M. & Hoglund, P. Quantifying the reduction in accessibility of the inhibitory NK cell receptor Ly49A caused by binding MHC class I proteins in cis. Eur. J. Immunol. 37, 516–527 (2007).

    Article  CAS  Google Scholar 

  36. Kim, S. et al. Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 436, 709–713 (2005).

    Article  CAS  Google Scholar 

  37. Cosman, D. et al. A novel immunoglobulin superfamily receptor for cellular and viral MHC class I molecules. Immunity 7, 273–282 (1997).

    Article  CAS  Google Scholar 

  38. Hayami, K. et al. Molecular cloning of a novel murine cell-surface glycoprotein homologous to killer cell inhibitory receptors. J. Biol. Chem. 272, 7320–7327 (1997).

    Article  CAS  Google Scholar 

  39. Takai, T. A novel recognition system for MHC class I molecules constituted by PIR. Adv. Immunol. 88, 161–192 (2005).

    Article  CAS  Google Scholar 

  40. Willcox, B. E., Thomas, L. M. & Bjorkman, P. J. Crystal structure of HLA-A2 bound to LIR-1, a host and viral major histocompatibility complex receptor. Nature Immunol. 4, 913–919 (2003).

    Article  CAS  Google Scholar 

  41. Nakamura, A., Kobayashi, E. & Takai, T. Exacerbated graft-versus-host disease in Pirb−/− mice. Nature Immunol. 5, 623–629 (2004).

    Article  CAS  Google Scholar 

  42. Wu, H., Kwong, P. D. & Hendrickson, W. A. Dimeric association and segmental variability in the structure of human CD4. Nature 387, 527–530 (1997).

    Article  CAS  Google Scholar 

  43. Meijers, R. et al. Structural basis of Dscam isoform specificity. Nature 449, 487–491 (2007).

    Article  CAS  Google Scholar 

  44. Lanier, L. L. NK cell recognition. Annu. Rev. Immunol. 23, 225–274 (2005).

    Article  CAS  Google Scholar 

  45. Boyington, J. C., Motyka, S. A., Schuck, P., Brooks, A. G. & Sun, P. D. Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand. Nature 405, 537–543 (2000).

    Article  CAS  Google Scholar 

  46. Fan, Q. R., Long, E. O. & Wiley, D. C. Crystal structure of the human natural killer cell inhibitory receptor KIR2DL1–HLA-Cw4 complex. Nature Immunol. 2, 452–460 (2001).

    Article  CAS  Google Scholar 

  47. Khakoo, S. I. et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 305, 872–874 (2004).

    Article  CAS  Google Scholar 

  48. Li, P. et al. Complex structure of the activating immunoreceptor NKG2D and its MHC class I-like ligand MICA. Nature Immunol. 2, 443–451 (2001).

    Article  CAS  Google Scholar 

  49. Sullivan, L. C. et al. The heterodimeric assembly of the CD94-NKG2 receptor family and implications for human leukocyte antigen-E recognition. Immunity 27, 900–911 (2007).

    Article  CAS  Google Scholar 

  50. Wada, H., Matsumoto, N., Maenaka, K., Suzuki, K. & Yamamoto, K. The inhibitory NK cell receptor CD94/NKG2A and the activating receptor CD94/NKG2C bind the top of HLA-E through mostly shared but partially distinct sets of HLA-E residues. Eur. J. Immunol. 34, 81–90 (2004).

    Article  CAS  Google Scholar 

  51. Lebron, J. A. et al. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell 93, 111–123 (1998).

    Article  CAS  Google Scholar 

  52. Bennett, M. J., Lebron, J. A. & Bjorkman, P. J. Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor. Nature 403, 46–53 (2000). This paper reports a co-crystal structure that reveals an association of the non-classical MHC class I molecule HFE with the TfR on the same membrane.

    Article  CAS  Google Scholar 

  53. Rohrlich, P. S. et al. Direct recognition by αβ cytolytic T cells of Hfe, a MHC class Ib molecule without antigen-presenting function. Proc. Natl Acad. Sci. USA 102, 12855–12860 (2005).

    Article  CAS  Google Scholar 

  54. Mitra, A. K. et al. Supine orientation of a murine MHC class I molecule on the membrane bilayer. Curr. Biol. 14, 718–724 (2004).

    Article  CAS  Google Scholar 

  55. Veillette, A., Latour, S. & Davidson, D. Negative regulation of immunoreceptor signaling. Annu. Rev. Immunol. 20, 669–707 (2002).

    Article  CAS  Google Scholar 

  56. Blery, M. et al. Reconstituted killer cell inhibitory receptors for major histocompatibility complex class I molecules control mast cell activation induced via immunoreceptor tyrosine-based activation motifs. J. Biol. Chem. 272, 8989–8996 (1997).

    Article  CAS  Google Scholar 

  57. Lanier, L. L., Corliss, B. & Phillips, J. H. Arousal and inhibition of human NK cells. Immunol. Rev. 155, 145–154 (1997).

    Article  CAS  Google Scholar 

  58. Eriksson, M., Ryan, J. C., Nakamura, M. C. & Sentman, C. L. Ly49A inhibitory receptors redistribute on natural killer cells during target cell interaction. Immunology 97, 341–347 (1999).

    Article  CAS  Google Scholar 

  59. Olsson-Alheim, M. Y., Salcedo, M., Ljunggren, H.-G., Kärre, K. & Sentman, C. L. NK cell receptor calibration. Effects of MHC class I induction on killing by Ly49Ahigh and Ly49Alow NK cells. J. Immunol. 159, 3189–3194 (1997).

    CAS  PubMed  Google Scholar 

  60. Olsson, M. Y., Karre, K. & Sentman, C. L. Altered phenotype and function of natural killer cells expressing the major histocompatibility complex receptor Ly-49 in mice transgenic for its ligand. Proc. Natl Acad. Sci. USA 92, 1649–1653 (1995).

    Article  CAS  Google Scholar 

  61. Kawakami, T. & Galli, S. J. Regulation of mast-cell and basophil function and survival by IgE. Nature Rev. Immunol. 2, 773–786 (2002).

    Article  CAS  Google Scholar 

  62. Katz, H. R. Inhibitory receptors and allergy. Curr. Opin. Immunol. 14, 698–704 (2002).

    Article  CAS  Google Scholar 

  63. Ho, L. H., Uehara, T., Chen, C. C., Kubagawa, H. & Cooper, M. D. Constitutive tyrosine phosphorylation of the inhibitory paired Ig-like receptor PIR-B. Proc. Natl Acad. Sci. USA 96, 15086–15090 (1999).

    Article  CAS  Google Scholar 

  64. Colonna, M. et al. Human myelomonocytic cells express an inhibitory receptor for classical and nonclassical MHC class I molecules. J. Immunol. 160, 3096–3100 (1998).

    CAS  PubMed  Google Scholar 

  65. Soderberg-Naucler, C., Fish, K. N. & Nelson, J. A. Reactivation of latent human cytomegalovirus by allogeneic stimulation of blood cells from healthy donors. Cell 91, 119–126 (1997).

    Article  CAS  Google Scholar 

  66. Crocker, P. R., Paulson, J. C. & Varki, A. Siglecs and their roles in the immune system. Nature Rev. Immunol. 7, 255–266 (2007).

    Article  CAS  Google Scholar 

  67. Razi, N. & Varki, A. Masking and unmasking of the sialic acid-binding lectin activity of CD22 (Siglec-2) on B lymphocytes. Proc. Natl Acad. Sci. USA 95, 7469–7474 (1998). This is one of the first demonstrations that immunoreceptors (CD22) can be masked by ligand (sialic acid) expression on the same cell.

    Article  CAS  Google Scholar 

  68. Collins, B. E. et al. Constitutively unmasked CD22 on B cells of ST6Gal I knockout mice: novel sialoside probe for murine CD22. Glycobiology 12, 563–571 (2002). In this paper it is shown that CD22 can switch from a cis - to a trans - bound state on cell–cell interactions. This is not observed with cis - bound Ly49A (see reference 34).

    Article  CAS  Google Scholar 

  69. O'Keefe, T. L., Williams, G. T., Davies, S. L. & Neuberger, M. S. Hyperresponsive B cells in CD22-deficient mice. Science 274, 798–801 (1996).

    Article  CAS  Google Scholar 

  70. Poe, J. C. et al. CD22 regulates B lymphocyte function in vivo through both ligand-dependent and ligand-independent mechanisms. Nature Immunol. 5, 1078–1087 (2004).

    Article  CAS  Google Scholar 

  71. Lanoue, A., Batista, F. D., Stewart, M. & Neuberger, M. S. Interaction of CD22 with α2,6-linked sialoglycoconjugates: innate recognition of self to dampen B cell autoreactivity? Eur. J. Immunol. 32, 348–355 (2002).

    Article  CAS  Google Scholar 

  72. Collins, B. E. et al. Masking of CD22 by cis ligands does not prevent redistribution of CD22 to sites of cell contact. Proc. Natl Acad. Sci. USA 101, 6104–6109 (2004).

    Article  CAS  Google Scholar 

  73. Egea, J. & Klein, R. Bidirectional Eph–ephrin signaling during axon guidance. Trends Cell Biol. 17, 230–238 (2007).

    Article  CAS  Google Scholar 

  74. Yin, Y. et al. EphA receptor tyrosine kinases interact with co-expressed ephrin-A ligands in cis. Neurosci. Res. 48, 285–296 (2004).

    Article  CAS  Google Scholar 

  75. Arase, H., Mocarski, E. S., Campbell, A. E., Hill, A. B. & Lanier, L. L. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296, 1323–1326 (2002).

    Article  CAS  Google Scholar 

  76. Gays, F. et al. Ly49B is expressed on multiple subpopulations of myeloid cells. J. Immunol. 177, 5840–5851 (2006).

    Article  CAS  Google Scholar 

  77. Toyama-Sorimachi, N. et al. Ly49Q, a member of the Ly49 family that is selectively expressed on myeloid lineage cells and involved in regulation of cytoskeletal architecture. Proc. Natl Acad. Sci. USA 101, 1016–1021 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Work in the authors' laboratories is supported in part by grants from the Swiss National Science Foundation and Oncosuissse (to W.H.) and the National Institutes of Health, USA (AI047990 to R.A.M.). We thank S. Cho for assistance with preparation of the original figures.

Author information

Authors and Affiliations

  1. Ludwig Institute for Cancer Research, Lausanne Branch and University of Lausanne, Chemin des Boveresses 155, 1066, Epalinges, Switzerland

    Werner Held

  2. Center for Advanced Research in Biotechnology, WM Keck Laboratory for Structural Biology, University of Maryland Biotechnology Institute, Rockville, 20850, Maryland, USA

    Roy A. Mariuzza

  3. Roy A. Mariuzza

Authors
  1. Werner Held
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roy A. Mariuzza
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

DATABASES

Protein Data Bank

1A6Z

1MI5

1P4L

1P7Q

1QO3

FURTHER INFORMATION

Werner Held's homepage

Roy Mariuzza's homepage

Glossary

'Missing-self' hypothesis

The concept that absence of MHC class I expression renders host cells sensitive to lysis by natural killer cells.

Positive selection

One step in the process of T-cell differentiation in the thymus. Thymocytes expressing T-cell receptors with moderate affinity for self-peptide–MHC complexes receive a survival signal and continue to develop towards becoming single positive (CD4+CD8− or CD4−CD8+) T cells. Positive selection is mediated by resident stromal cells in the thymic cortex.

Type II membrane proteins

An integral membrane protein, such as Ly49, in which the carboxy terminus is extracellular.

C-type lectin-like domain

(CTLD). A protein module originally identified as a carbohydrate-recognition domain in a family of calcium-dependent lectins. The natural-killer-cell receptor group of C-type lectin-like receptors includes disulphide-linked homodimers or heterodimers that do not bind calcium and recognize proteins instead of carbohydrates.

HLA-E

A non-classical MHC class I molecule with limited sequence variability. Its expression on the cell surface depends on the availability of peptides derived from the signal sequence of classical MHC class I molecules. HLA-E is recognized by CD94–NKG2 receptors.

Qa-1b

A functional mouse homologue of human HLA-E. Similar to HLA-E, Qa-1b cell-surface expression depends on the binding of peptides derived from the signal sequence of classical MHC class I molecules and it is recognized by CD94–NKG2 receptors.

Haemochromatosis protein

(HFE). A non-classical MHC class I molecule that regulates iron metabolism by binding to the transferrin receptor. The HFE gene is mutated in hereditary haemochromatosis — an iron overload disease.

Immunoreceptor tyrosine-based inhibitory motif

(ITIM). A short amino-acid sequence (the consensus sequence of which is Val/Ile-X-Tyr-X-X-Val/Leu, where X denotes any amino acid) that is found in the cytoplasmic tail of inhibitory receptors. ITIMs are thought to mediate inhibitory signalling by recruiting phosphatases such as SHP1 (SRC-homology-2-domain-containing protein tyrosine phosphatase 1).

Immunological synapse

A term derived from the similiarities to the synapses that occur in the nervous system, it defines a region that can form at the cell surface between two cells of the immune system that are in close contact, such as the interaction between a T cell and a natural killer cell with an antigen-presenting cell and a target cell, respectively. This interface involves adhesion molecules, as well as antigen receptors and cytokine receptors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Held, W., Mariuzza, R. Cis interactions of immunoreceptors with MHC and non-MHC ligands. Nat Rev Immunol 8, 269–278 (2008). https://doi.org/10.1038/nri2278

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2278

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing