The involvement of HLA-E and -F in pregnancy

doi:10.1016/j.jri.2005.10.004

Journal of Reproductive Immunology

Volume 69, Issue 2, April 2006, Pages 101-113

https://doi.org/10.1016/j.jri.2005.10.004 Get rights and content

Abstract

The human MHC class I genes, HLA-E, -F and -G are referred to as non-classical or class Ib genes and are distinguished from their close relatives (the classical HLA class I genes) by expression patterns and low allelic polymorphism. To date, most studies that relate these molecules to the immunology of pregnancy have concerned only HLA-G. However, recent advances have suggested potential unique roles as well for HLA-E and HLA-F in pregnancy. A notable advance was the observation that all three proteins are expressed on the surface of extravillous trophoblast that has invaded the maternal decidua. Given this expression site, possibly the only cell type in human development where this occurs, it is logical to hypothesize that all three antigens, each with its own unique receptor–ligand interaction(s), contribute collectively to enable the growth of the developing child. In this review, we examine and discuss the accumulated data on expression and function of HLA-E and HLA-F and attempt to relate what is known to the involvement of HLA-E and -F in human pregnancy.

Section snippets

Identification of peptide binding to HLA-E

In the first examination of HLA-E, -F and -G protein expression, each of these three genes was transfected into the class I null cell line .221 (Shimizu et al., 1988). Of the three, only HLA-G was expressed on the surface, while HLA-E and -F were present intracellularly. To determine the signals controlling cell surface expression of HLA-E, hybrid genes were constructed and one containing the signal sequence of the HLA-A2 gene substituting in the HLA-E gene (designated AEH) was expressed on the

Interaction of HLA-E with CD94/NKG2 receptors on NK cells

In 1998, the interaction of HLA-E with CD94/NKG2 receptors was reported simultaneously by three groups. The HLA-E complex, with bound peptides derived from other HLA class I signal sequences, were shown to interact with CD94/NKG2 heterodimers on NK cells and inhibit the killing activity of NK cells (Lee et al., 1998b, Borrego et al., 1998). Although CD94/NKG2 C-type lectin receptors had been thought at that time to interact with class 1a molecules, it was shown that the ligand of CD94/NKG2 was

HLA-E allelic polymorphism

Two non-synonymous alleles of HLA-E have been confirmed (Grimsley et al., 2002), referred to as HLA-E^R (E*0101) and HLA-E^G (E*0103) (Geraghty et al., 1992) since they are distinguished by having either an arginine (-E^R) or a glycine (-E^G) at position 107 of the protein. HLA-E^G and -E^R are found at nearly equal frequencies in diverse populations, a strong indication that balancing selection has been operating on the locus and implying functional differences exist between the two alleles. In a

HLA-E can bind peptides derived from other sources

Although HLA-E was originally described as binding only peptides derived from the signal sequence of HLA class I molecules, recent reports have suggested that HLA-E can also bind and present peptides from virus, mycobacterium or heat shock protein (Hsp) 60. Tomasec et al. (2000) found that HLA-E surface expression was upregulated by infection with human cytomegalovirus (HCMV). They found that a peptide with identical sequence to a nonamer peptide from HLA class I molecules was found in the

Are diverse HLA-E bound peptides capable of providing a complex that can interact with CD94/NKG2 receptors?

Nattermann et al., 2005a, Nattermann et al., 2005b reported that HLA-E-bound peptides derived from HCV and HIV inhibited cytotoxicity of NK cell through CD94/NKG2, and concluded that enhanced HLA-E expression was likely to be functionally relevant concerning down-regulation of NK cell activity during chronic hepatitis C infection. It is well known that the expression of HLA class Ia molecules are down-regulated by specific proteins produced by HCMV and HIV during infection. Such down-regulation

HLA-E may also present peptide to CD8⁺ cytotoxic T cells (CTL)

Recent reports have suggested that specific HLA-E/peptide complexes can induce not only the inhibition of NK cells through CD94/NKG2 receptors, but also the activation of cytotoxicity of CD8⁺ T cells through an interaction with the T cell receptor. Pietra et al. (2001) identified a fraction of human CD8⁺ CTL, which lysed certain NK-susceptible target cells via still undefined mechanism(s). These CD8⁺ T cells, referred to as NK-CTL, are frequently composed of cells expressing one single TCR Vβ

HLA-F expression and function

Geraghty et al. (1990) first identified the HLA-F gene and suggested that HLA-F was expressed as a β2-microglobulin-associated protein of 40–41 kDa. The protein was shorter than typical HLA class I due to the exclusion of exon 7 from the mature HLA-F mRNA, yielding a protein with a shortened cytoplasmic domain. Significant structural differences from the canonical HLA class I structure were suggested due to alterations in 5 of 10 residues found to be highly conserved in other MHC class I

Interaction with NK cells in decidua

In human pregnancy, semiallogenic fetal cells (trophoblast) invade into the decidua, and fuse with and open up maternal uterine arteries in order to facilitate an adequate supply of blood to the developing fetus through an interaction with decidual NK cells. The extravillous trophoblast (EXT) invading maternal decidua have a unique immunological phenotype compared to most cells, especially with regard to their expression of HLA. They express only class Ib, HLA-E, -F and -G (Ishitani et al., 2003

Conclusion

The first observation of HLA-F surface expression in vivo was on EXT invading maternal decidua in term placenta using double fluorescence immunohistochemical staining with anti-HLA-F and anti-HLA-G antibodies (Ishitani et al., 2003). This result, and the demonstration of coexpression of HLA-E, -F and -G on EXT that had invaded the maternal decidua, forms the nexus of this review and we believe provides an important segue into an evolving view of the role of the non-classical class I antigens in

References (52)

M.A. Cooper et al.
Human natural killer cells: a unique innate immunoregulatory role for the CD56^bright subset
Blood
(2001)
D.E. Geraghty et al.
Polymorphism at the HLA-E locus predates most HLA-A and -B polymorphism
Hum. Immunol.
(1992)
A. King et al.
Surface expression of HLA-C antigen by human extravillous trophoblast
Placenta
(2000)
J. Nattermann et al.
The HLA-A2 restricted T cell epitope HCV core 35–44 stabilizes HLA-E expression and inhibits cytolysis mediated by natural killer cells
Am. J. Pathol.
(2005)
S. Saito
Cytokine network at the feto–maternal interface
J. Reprod. Immunol.
(2000)
R.K. Strong et al.
HLA-E allelic variants. Correlating differential expression, peptide affinities, crystal structures, and thermal stabilities
J. Biol. Chem.
(2003)
J.J. Van Rood et al.
Both self and non-inherited maternal HLA antigens influence the immune response
Immunol. Today
(2000)
A.A. Ashkar et al.
Assessment of requirements for IL-15 and IFN regulatory factors in uterine NK cell differentiation and function during pregnancy
J. Immunol.
(2003)
A. Barakonyi et al.
The role of gamma/delta T-cell receptor-positive cells in pregnancy. Part II
Am. J. Reprod. Immunol.
(1999)
A. Barakonyi et al.
Recognition of nonclassical HLA class I antigens by gamma delta T cells during pregnancy
J. Immunol.
(2002)

F. Borrego et al.

Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed cell with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer c ell-mediated lysis

J. Exp. Med.

(1998)

V.M. Braud et al.

HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C

Nature

(1998)

M. Colonna et al.

Human myelomonocytic cells express an inhibitory receptor for classical and non-classical MHC class I molecules

J. Immunol.

(1998)

P. Contini et al.

Soluble HLA-A,-B -C and -G molecules induce apoptosis in T and NK CD8+ cells and inhibit cytotoxic T cell activity through CD8 ligation

Eur. J. Immunol.

(2003)

C.S. Falk et al.

NK cell activity during human cytomegalovirus infection is dominated by US2-11-mediated HLA class I down-regulation

J. Immunol.

(2002)

S.M. Fournel et al.

Cutting edge: soluble HLA-G1 triggers CD95/CD95 ligand-mediated apoptosis in activated CD8+ cells by interacting with CD8

J. Immunol.

(2000)

D.E. Geraghty et al.

A human major histocompatibility complex class I gene that encodes a protein with a shortened cytoplasmic segment

Proc. Natl. Acad. Sci. U.S.A.

(1987)

D.E. Geraghty et al.

Human leukocyte antigen F (HLA-F) An expressed HLA gene composed of a class I coding sequence linked to a novel transcribed repetitive element

J. Exp. Med.

(1990)

C. Grimsley et al.

Definitive high resolution typing of HLA-E allelic polymorphisms: Identifying potential errors in existing allele data

Tissue Antigens

(2002)

A.S. Heinzel et al.

HLA-E-dependent presentation of Mtb-derived antigen to human CD8+ T cells

J. Exp. Med.

(2002)

S. Higuma-Myojo et al.

Cytokine profile of natural killer cells in early human pregnancy

Am. J. Reprod. Immunol.

(2005)

N. Hirankarn et al.

HLA-E polymorphism in patients with nasopharyngeal carcinoma

Tissue Antigens

(2004)

A. Ishitani et al.

Alternative splicing of HLA-G transcripts yields proteins with primary structures resembling both class I and class II antigens

Proc. Natl. Acad. Sci. U.S.A.

(1992)

A. Ishitani et al.

Protein expression and peptide binding suggest unique and interacting functional roles for HLA-E, F, and G in maternal-placental immune recognition

J. Immunol.

(2003)

B.K. Kaiser et al.

Interactions between NKG2x immunoreceptors and HLA-E ligands display overlapping affinities and thermodynamics

J. Immunol.

(2005)

B.H. Koller et al.

HLA-E. A novel HLA class I gene expressed in resting T lymphocytes

J. Immunol.

(1988)

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Mini-reviewThe involvement of HLA-E and -F in pregnancy

Abstract

Section snippets

Identification of peptide binding to HLA-E

Interaction of HLA-E with CD94/NKG2 receptors on NK cells

HLA-E allelic polymorphism

HLA-E can bind peptides derived from other sources

Are diverse HLA-E bound peptides capable of providing a complex that can interact with CD94/NKG2 receptors?

HLA-E may also present peptide to CD8+ cytotoxic T cells (CTL)

HLA-F expression and function

Interaction with NK cells in decidua

Conclusion

Blood

Hum. Immunol.

Placenta

Am. J. Pathol.

J. Reprod. Immunol.

J. Biol. Chem.

Immunol. Today

Assessment of requirements for IL-15 and IFN regulatory factors in uterine NK cell differentiation and function during pregnancy

J. Immunol.

The role of gamma/delta T-cell receptor-positive cells in pregnancy. Part II

Am. J. Reprod. Immunol.

Recognition of nonclassical HLA class I antigens by gamma delta T cells during pregnancy

J. Immunol.

Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed cell with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer c ell-mediated lysis

J. Exp. Med.

HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C

Nature

Human myelomonocytic cells express an inhibitory receptor for classical and non-classical MHC class I molecules

J. Immunol.

Soluble HLA-A,-B -C and -G molecules induce apoptosis in T and NK CD8+ cells and inhibit cytotoxic T cell activity through CD8 ligation

Eur. J. Immunol.

NK cell activity during human cytomegalovirus infection is dominated by US2-11-mediated HLA class I down-regulation

J. Immunol.

Cutting edge: soluble HLA-G1 triggers CD95/CD95 ligand-mediated apoptosis in activated CD8+ cells by interacting with CD8

J. Immunol.

A human major histocompatibility complex class I gene that encodes a protein with a shortened cytoplasmic segment

Proc. Natl. Acad. Sci. U.S.A.

Human leukocyte antigen F (HLA-F) An expressed HLA gene composed of a class I coding sequence linked to a novel transcribed repetitive element

J. Exp. Med.

Definitive high resolution typing of HLA-E allelic polymorphisms: Identifying potential errors in existing allele data

Tissue Antigens

HLA-E-dependent presentation of Mtb-derived antigen to human CD8+ T cells

J. Exp. Med.

Cytokine profile of natural killer cells in early human pregnancy

Am. J. Reprod. Immunol.

HLA-E polymorphism in patients with nasopharyngeal carcinoma

Tissue Antigens

Alternative splicing of HLA-G transcripts yields proteins with primary structures resembling both class I and class II antigens

Proc. Natl. Acad. Sci. U.S.A.

Protein expression and peptide binding suggest unique and interacting functional roles for HLA-E, F, and G in maternal-placental immune recognition

J. Immunol.

Interactions between NKG2x immunoreceptors and HLA-E ligands display overlapping affinities and thermodynamics

J. Immunol.

HLA-E. A novel HLA class I gene expressed in resting T lymphocytes

J. Immunol.

Mini-review
The involvement of HLA-E and -F in pregnancy

HLA-E may also present peptide to CD8⁺ cytotoxic T cells (CTL)