Non‐Classical MHC Class I Molecules (MHC‐Ib)

Abstract

Major histocompatibility complex class I (MHC‐I) molecules are a family of structurally related proteins that were first characterised through their central role in adaptive immunity. Classical MHC class I (MHC‐Ia) molecules comprise a heavy chain complexed with β2m to display short peptide fragments on the surface of all nucleated cells. As antigen‐presenting proteins, the classical role of MHC‐Ia is to present these peptides for recognition by T‐cell receptors expressed by cytotoxic T‐cells. MHC‐Ia are also recognised by innate immune receptors on other leukocyte subsets. A diverse group of structurally related proteins, collectively termed nonclassical MHC class I molecules or MHC‐Ib, exists to perform a range of alternative immune roles. Here, the authors describe the biology of human MHC‐Ib molecules and their recognition as antigen‐presenting and antigen‐independent ligands for various immune receptors.

Key Concepts:

  • Classical MHC class I (MHC‐Ia) are highly polymorphic proteins which, together with β2m, form a structure that presents short peptide antigens for recognition by the classical αβ T‐cell receptor (TCR) on CD8+ T‐cells.

  • MHC‐Ia proteins also exist in nonclassical forms – MHC‐I heavy chain structures lacking β2m are found on the surface of activated immune cells, where they are recognised by alternative immune receptors such as members of the leukocyte Ig‐like (LILR) family.

  • Nonclassical MHC‐Ib are usually nonpolymorphic and tend to show a more restricted pattern of expression than their MHC‐Ia counterparts.

  • MHC‐Ib may be recognised by specific subsets of T‐cell receptors or by innate immune receptors.

  • Owing to their recognition by a more restricted set of receptors, MHC‐Ib are able to elicit a rapid response from immune cells and are, therefore, regarded as part of the innate immune system.

  • Some MHC‐Ib act as antigen presenting structures, whereas others are recognised as direct ligands for immune receptors.

Keywords: MHC‐Ib; HLA‐E; HLA‐F; HLA‐G; CD1; MICA; MICB; ULBP; NKT cells; γδ T‐cells

Figure 1.

MHC‐Ia. Within the MHC‐Ia structure, the antigen‐binding groove is formed by the α1 and α2 domains of the MHC‐I heavy chain. Individual pockets within the groove are defined by biochemical characteristics, which, in turn, determine the nature of the peptide ligands that can be anchored within them. The classical αβ T‐cell Receptor (TCR) binds diagonally across the antigen‐binding groove. This orientation allows the receptor to recognise both the MHC‐I protein itself and the antigenic peptide presented within the groove. The α3 domain and β2m provide structural support for the antigen‐binding groove in addition to forming binding sites for other receptors such as CD8 and LILR.

Figure 2.

HLA‐E. The overall structure of HLA‐E is very similar to that for classical MHC‐Ia. A defining feature of this MHC‐Ib protein is that strict structural constraints within the antigen‐binding groove restrict the repertoire of peptides that can be bound.

Figure 3.

HLA‐F. Relatively little is known about this MHC‐encoded protein. Although it associates with β2m, this MHC‐Ib protein does not appear to play any role in antigen presentation. To date, the only known receptors for HLA‐F are members of the LILR family.

Figure 4.

HLA‐G. HLA‐G exists in multiple isoforms and shows a restricted tissue distribution. The standard form of HLA‐G is similar to that of MHC‐Ia alleles, although structural constraints limit the repertoire of peptides that can bind within the antigen‐binding groove.

Figure 5.

Hfe. This MHC‐Ib protein associates with β2m but does not appear to play any role in antigen presentation. Rather than immune function, the principal activity of Hfe is in Iron regulation.

Figure 6.

MICA and MICB. MIC proteins do not associate with β2m and do not appear to play a role in antigen presentation. These transmembrane proteins are upregulated in response to stress stimuli.

Figure 7.

ULBPs. Like their MIC counterparts, ULBPs do not play a role in antigen presentation. ULBPs do not associate with β2m and consist of α1 and α2 domains linked to the cell surface by a GPI tail.

Figure 8.

CD1. CD1 molecules are antigen‐presenting MHC‐Ib proteins, which bind glycolipid or phospholipid antigens within their binding groove and present these for recognition by receptors on NKT cells. They are expressed by professional antigen‐presenting cells.

Figure 9.

MR1. MR1 is an antigen‐presenting MHC‐Ib protein, which presents nonpeptide antigens. These ligands are recognised by receptors on MAIT.

Figure 10.

EPCR. This MHC‐Ib protein resembles CD1 and presents phospholipids for recognition by γδ T‐cells. It does not associate with β2m and consists of α1 and α2 domains linked to the cell surface by a transmembrane domain.

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References

Adams EJ (2013) Diverse antigen presentation by the Group 1 CD1 molecule CD1d. Molecular Immunology 55: 182–185.

Anderson KJ and Allen RL (2009) Regulation of T‐cell immunity by leucocyte immunoglobulin‐like receptors: innate immune receptors for self on antigen presenting cells. Immunology 127: 8–17.

Arosa FA, Santos SG and Powis SJ (2007) Open conformers: the hidden face of MHC‐I molecules. Trends in Immunology 28: 115–123.

Bennet MJ, Lebron JA and Bjorkman PJ (2000) Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor. Nature 403: 46–53.

Bonarius HP, Baas F, Remmerswaal EB et al. (2006) Monitoring the T‐cell receptor repertoire at single‐clone resolution. PLoS ONE 1(1): e55. doi:10.1371/journal.pone.0000055.

Braud VM, Allan DS, O'Callaghan CA et al. (1998) HLA‐E binds to natural killer receptors CD94/NKG2A B and C. Nature 391: 795–799.

Bukur J, Jasinski S and Seliger B (2012) The role of classical and non‐classical HLA antigens in human tumours. Seminars in Cancer Biology 22: 350–358.

Carosella ED, Gregori S and LeMaoult J (2011) The tolerogenic interplay(s) among HLA‐G, myeloid APCs, and regulatory cells. Blood 118: 6499–6505.

Carosella ED, Gregori S, Rouas‐Freiss N et al. (2011a) The role of HLA‐G in immunity and hematopoiesis. Cellular and Molecular Life Sciences 68: 353–368.

Chien YH and Konigshofer Y (2007) Antigen recognition by gammadelta T cells. Immunology Reviews 215: 46–58.

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

De Jong A, Pena‐Cruz V, Cheng TY et al. (2010) CD1a‐autoreactive T cells are a normal component of the human ab T cell repertoire. Nature Immunology 11: 1102–1109.

De la Salle H, Mariotti SM, Angenieux CM et al. (2005) Assistance of microbial glycolipid antigen processing by CD1e. Science 310: 1321–1324.

Drakesmith H and Prentice A (2008) Viral infection and iron metabolism. Nature Reviews Microbiology 6: 541–542.

Fernandez‐Messina L, Reyburn HT and Vales‐Gomez M (2012) Human NKG2D ligands: cell biology strategies to ensure immune regulation. Frontiers in Immunology 3: 299.

Garcia KC, Degano M, Stanfield RL et al. (1996) An alphabeta T cell receptor structure at 2.5 A and its orientation in the TCR‐MHC complex. Science 274: 209–219.

Girardi E, Maricic I, Wang J et al. (2012) Type II natural killer T cells use features of both innate‐like and conventional T cells to recognise sulfatide self‐antigens. Nature Immunology 13: 851–856.

Gold MC, Cerri S, Smyk‐Pearson S et al. (2010) Human mucosal‐associated invariant T cells detect bacterially infected cells. PLoS Biology 8: e1000407.

Goodridge JP, Burian A, Lee N and Geraghty DE (2010) HLA‐F complex without peptide binds to MHC class I protein in the open conformer form. Journal of Immunology 184: 6199–6208.

Groh V, Bahram S, Bauer S et al. (1996) Cell stress‐regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proceedings of the National Academy of Sciences of the USA 93: 12445–12450.

Groh V, Steinle A, Bauer S and Spies T (1998) Recognition of stress‐induced MHC molecules by intestinal epithelial gammadelta T cells. Science 279: 1737–1740.

Groh V, Rhinehart R, Secrist H et al. (1999) Broad tumor‐associated expression and recognition by tumor‐derived gamma delta T cells of MICA and MICB. Proceedings of the National Academy of Sciences of the USA 96: 6879–6884.

Hoare HL, Sullivan LC, Clements CS et al. (2008) Subtle changes in peptide conformation profoundly affect recognition of the non‐classical MHC class I molecule HLA‐E by the CD94‐NKG2 natural killer cell receptors. Journal of Molecular Biology 377: 1297–1303.

Hofstetter AR, Sullivan LC, Lukacher AE and Brooks AG (2011) Diverse roles of non‐diverse molecules: MHC class Ib molecules in host defense and control of autoimmunity. Current Opinion in Immunology 23: 104–110.

Im JS, Arora P, Bricard G et al. (2009) Kinetics and cellular site of glycolipid loading control the outcome of natural killer T cell activation. Immunity 30: 888–898.

Iwaszko M and Bogunia‐Kubik K (2011) Clinical significance of the HLA‐E and CD94/NKG2 interaction. Archivum Immunologiae et Therapiae Experimentalis 59: 353–367.

Jacobs EM, Verbeek AL, Kreeftenberg HG et al. (2007) Changing aspects of HFe‐related hereditary haemochromatosis and endeavours to early diagnosis. Netherlands Journal of Medicine 65: 419–424.

Jones DC, Kosmoliaptsis V, Apps R et al. (2012) HLA class I allelic sequence and conformation regulate leukocyte Ig‐like receptor binding. Journal of Immunology 186: 2990s–2997s.

Kawano T, Cui J, Koezuka Y et al. (1997) CD1d‐restricted and TCR‐mediated activation of valpha14 NKT cells by glycosylceramides Science 278: 1626–1629.

Kjer‐Nielson L, Patel O, Corbett AJ et al. (2012) MR1 presents microbial vitamin B metabolites to MAIT T cells. Nature 10.1038/nature11605

Kumanovcis A, Takada T and Fischer‐Lindahl K (2003) Genomic organisation of the mammalian MHC. Annual Review of Immunology 21: 629–657.

Le Bourhis L, Guerri L, Dusseaux M et al. (2011) Mucosal‐associated invariant T cells: unconventional development and function. Trends in Immunology 32: 212–218.

Lee N, Ishitani A and Geraghty DE (2010) HLA‐F is a surface marker on activated lymphocytes. European Journal of Immunology 40: 2308–2318.

Lee N, Llano M, Carretero M et al. (1998) HLA‐E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proceedings of the National Academy of Sciences of the USA 95: 5199–5204.

Lepin EJ, Bastin JM, Allan DS et al. (2000) Functional characterization of HLA‐F and binding of HLA‐F tetramers to ILT2 and ILT4 receptors. European Journal of Immunology 30: 3552–3561.

O'Callaghan CA, Tormo J, WIllcox BE et al. (1998) Structural features impose tight peptide binding specificity in the non‐classical MHC molecule HLA‐E. Molecular Cell 1: 531–541.

Pei B, Vela JL, Zajonc D and Kronenberg M (2012) Interplay between carbohydrate and lipid in recognition of glycolipid antigens by natural killer T cells. Annals of the New York Academy of Sciences 1253: 68–79.

Pilsbury LE, Allen RL and Vordermeier M (2010) Modulation of Toll like receptor activity by Leukocyte Ig‐like Receptors and their effects during bacterial infection. Mediators of Inflammation 2010: 536478.

Rajagopalan S and Long EO (2012) KIR2DL4 (CD158d): An activation receptor for HLA‐G. Frontiers in Immunology 3: 258.

Reantragoon R, Kjer‐Neilsen L, Patel O et al. (2012) Structural insight into MR1‐mediated recognition of the mucosal associated invariant T cell receptor. Journal of Experimental Medicine 209: 761–774.

Shiroishi M, Kuroki K, Ose T et al. (2006) . Efficient leukocyte Ig‐like receptor signalling and crystal structure of disulphide‐linked HLA‐G dimer. Journal of Chemical Biology 281: 10439–10447.

Sullivan LC, Clements CS, Rossjohn J and Brooks AG (2008) The major histocompatibility complex class Ib molecule HLA‐E at the interface between innate and adaptive immunity. Tissue Antigens 72: 415–424.

Trowsdale J (2001) Genetic and functional relationships between MHC and NK receptor genes. Immunity 15: 363–374.

Van Hall T, Oliveira CC, Joosten SA and Ottenhoff TH (2010) The other Janus face of Qa‐1 and HLA‐E: diverse peptide repertoires in times of stress. Microbes and Infection 12: 910–918.

Willcox CR, Pitard V, Netzer S et al. (2012) Cytomegalovirus and tumour stress surveillance by binding of a human gd T cell antigen receptor to endothelial protein C Receptor. Nature Immunology 13: 872–879.

Wu J, Groh V and Spies T (2002) T cell antigen receptor engagement and specificity in the recognition of stress‐inducible MHC class I‐related chains by human epithelial gamma delta T cells. Journal of Immunology 169: 1236–1240.

Xu B, Pizzaro JC, Holmes MA et al. (2011) Crystal structure of a γδ T‐cell receptor specific for the human MHC class I homolog MICA. Proceedings of the National Academy of Sciences of the USA 108: 2414–2419.

Zajonc DM and Kronenberg M (2007) CD1 mediated cell recognition of glycolipids. Current Opinion in Structural Biology 17: 521–529.

Zeisseg S and Blumberg RS (2011) Primary immunodeficiency associated with defects in CD1 and CD1‐restricted T cells. Annals of the New York Academy of Sciences 1250: 14–24.

Further Reading

Apps R, Gardner L and Moffett A (2008) A critical look at HLA‐G. Trends in Immunology 29: 313–321.

Hayday A (2000) [gamma][delta] cells: a right time and a right place for a conserved third way of protection. Annual Review of Immunology 18: 975–1026.

Kasahara M and Yoshida S (2012) Immunogenetics of the NKG2D ligand family. Immunogenetics 64: 855–867.

Willcox BE, Willcox CR, Dover LG and Besra G (2007) Structures and functions of microbial lipid antigens presented by CD1. Current Topics in Microbiology and Immunology 314: 73–110.

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Allen, Rachel L, and Hogan, L(Nov 2013) Non‐Classical MHC Class I Molecules (MHC‐Ib). In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024246]