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


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