HLA-F and MHC Class I Open Conformers Are Ligands for NK Cell Ig-like Receptors

Goodridge, Jodie P.; Burian, Aura; Lee, Ni; Geraghty, Daniel E.

doi:10.4049/jimmunol.1300081

Cited by 120 publications

(126 citation statements)

References 49 publications

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“…It is tempting to speculate that functionally analogous systems exist in mice and humans, whereby the CD94-NKG2 receptors exclusively bind HLA-E/Qa-1 b , whereas Ly49/KIR bind a more diverse but structurally related group of molecules extending into non-classical MHC ligands. It is interesting to note recent evidence suggests that the MHC-Ib HLA-F is a ligand for KIR3DL2 and KIR2DS4 (38). It is also possible that unlike MHC-Ia, where the need to present diverse peptide repertoires for T cell recognition has driven the acquisition of polymorphism, the capacity of a number of MHC-Ib to interact with immunoreceptors such as those of the Ly49 family may have served to limit their genetic diversification.…”

Section: Discussionmentioning

confidence: 99%

Recognition of the Major Histocompatibility Complex (MHC) Class Ib Molecule H2-Q10 by the Natural Killer Cell Receptor Ly49C

Sullivan

Berry

Sosnin

et al. 2016

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Recognition of the Major Histocompatibility Complex (MHC) Class Ib Molecule H2-Q10 by the Natural Killer Cell Receptor Ly49C

Sullivan

Berry

Sosnin

et al. 2016

Journal of Biological Chemistry

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“…As expected, mAbs to a conformed heavy chain epitope (W6/32) and to β 2 m (NAMB-1) coimmunoprecipitated β 2 m and HLA-E, respectively, particularly from 221.AEH cells (lanes 2, 3, 8, 9, 16, 17, 22, and 23). In contrast, mAbs to HLA-E (MEM-E/02, 3D12, and DT9) immunoprecipitated HLA-E heavy chains in comparable amounts (lanes 4-6 and 10-12), but only mAb 3D12 coimmunoprecipitated β 2 m in very low amounts and exclusively from 221.AEH cells (lanes [18][19][20][24][25][26]. Likewise, mAbs MEM-E/07 and MEM-E/08 did not detectably coimmunoprecipitate β 2 m (not shown, and see ref.…”

Section: Different Mabs Bind Different Hla-e Foldsmentioning

confidence: 99%

“…At least two groups have demonstrated that "open conformers" of classical class I heavy chains and HLA-F are sufficiently folded to engage innate immune receptors including LILRB, LILRA1, LILRA3 [24], KIR2DL2, and KIR2DS4 [25]. In this light, CD94:NKG2A blockade by mAb 3D12 [26] raises the issue of whether NK cells might also be regulated by the free HLA-E heavy chains present in the 3D12 molecular pool.…”

Section: Hla-e: Folding and Functionmentioning

confidence: 99%

Monoclonal antibodies to HLA‐E bind epitopes carried by unfolded β₂m‐free heavy chains

Tremante¹,

Monaco²,

Ingegnere³

et al. 2015

Eur J Immunol

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Since HLA-E heavy chains accumulate free of their light β 2 -microglobulin (β 2 m) subunit, raising mAbs to folded HLA-E heterodimers has been difficult, and mAb characterization has been controversial. Herein, mAb W6/32 and 5 HLA-E-restricted mAbs (MEM-E/02, MEM-E/07, MEM-E/08, DT9, and 3D12) were tested on denatured, acid-treated, and natively folded (both β 2 m-associated and β 2 m-free) HLA-E molecules. Four distinct conformations were detected, including unusual, partially folded (and yet β 2 m-free) heavy chains reactive with mAb DT9. In contrast with previous studies, epitope mapping and substitution scan on thousands of overlapping peptides printed on microchips revealed that mAbs MEM-E/02, MEM-E/07, and MEM-E/08 bind three distinct α1 and α2 domain epitopes. All three epitopes are linear since they span just 4-6 residues and are "hidden" in folded HLA-E heterodimers. They contain at least one HLA-E-specific residue that cannot be replaced by single substitutions with polymorphic HLA-A, HLA-B, HLA-C, HLA-F, and HLA-G residues. Finally, also the MEM-E/02 and 3D12 epitopes are spatially distinct. In summary, HLA-E-specific residues are dominantly immunogenic, but only when heavy chains are locally unfolded. Consequently, the available mAbs fail to selectively bind conformed HLA-E heterodimers, and HLA-E expression may have been inaccurately assessed in some previous oncology, reproductive immunology, virology, and transplantation studies.Keywords: Conformation r HLA-E r HLA-A r -B r -C r mAbs r β 2 -microglobulin (β 2 m) Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionBeing the ligand of both the conserved CD94/NKG2A immune receptor and the variable TCR, the oligomorphic HLA-E molecule bridges classical and nonclassical HLA class I antigens [1]. Often classified among the latter, HLA-E may rather be considered an inbetweener. This definition also applies to HLA-C, since this is the least polymorphic among classical (HLA-A, -B, -C) Correspondence: Dr. Patrizio Giacomini e-mail: giacomini@ifo.it class I antigens, and shares with HLA-E several unorthodox properties, such as selective peptide binding, poor association with β 2 m [2-4], and massive accumulation in a β 2 m-free form [5,6].Although often unappreciated, unfolded and β 2 m-free heavy chains may share epitopes with fully folded HLA class I heterodimers. These "intermediate" folds may confound the assignment of antibody specificity. For instance, a mAb called Q1/28 binds HLA-B but not HLA-C when heavy chains are β 2 massociated, and HLA-C but not HLA-B when heavy chains are β 2 m-free [7]. Likewise, mAbs MEM-E/07 and MEM-E/08 bind β 2 m-free HLA-E, but cross-react with HLA-A, -B, -C heavy chainswww.eji-journal.eu Eur. J. Immunol. 2015. 45: 2356-2364 Molecular immunology 2357 associated with β 2 m [6]. Therefore, mAbs to inbetweeners require thorough characterization, including their systematic testing on both the β 2 m-associated and the β 2 m-free heavy chains specified by ...

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“…HLA-I molecules have been implicated in interactions with other receptors both in trans and in cis, and the full-length HLA-I H chain can form a homodimer similar to HLA-A11svE4. Geraghty and colleagues (17)(18)(19)(20) showed that HLA-F and MHC-I OCs are devoid of b2m, but cooperate in a MHC-I Ag-crosspresentation pathway, although they also observed HLA-F and MHC-I OCs without Ags. Interestingly, they also proved that the OCs of HLA-F and MHC-I are ligands of KIR.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the authors showed that HLA-F and MHC-I OCs operate together in activated lymphocytes and monocytes in an Ag cross-presentation pathway, which suggested that complexes with two MHC-I H chains have the ability to present Ags (18). Furthermore, research has also shown that the OCs of HLA-F and MHC-I bind to KIR3DL2 to inhibit NK activation (19,20). Taken together, these results indicated that the OCs are functional in the immune system.…”

mentioning

confidence: 99%

α3-Deletion Isoform of HLA-A11 Modulates Cytotoxicity of NK Cells: Correlations with HIV-1 Infection of Cells

Zhang

Lian

Dai

et al. 2017

The Journal of Immunology

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Alternative splicing occurs frequently in many genes, especially those involved in immunity. Unfortunately, the functions of many alternatively spliced molecules from immunologically relevant genes remain unknown. Classical HLA-I molecules are expressed on almost all nucleated cells and play a pivotal role in both innate and adaptive immunity. Although splice variants of HLA-I genes have been reported, the details of their functions have not been reported. In the current study, we determined the characteristics, expression, and function of a novel splice variant of HLA-A11 named HLA-A11svE4. HLA-A11svE4 is located on the cell surface without b2-microglobulin (b2m). Additionally, HLA-A11svE4 forms homodimers as well as heterodimers with HLA-A open conformers, instead of combining with b2m. Moreover, HLA-A11svE4 inhibits the activation of NK cells to protect target cells. Compared with b2m and HLA-A11, the heterodimer of HLA-A11svE4 and HLA-A11 protected target cells from lysis by NK cells more effectively. Furthermore, HLA-AsvE4 expression was upregulated by HIV-1 in vivo and by HSV, CMV, and hepatitis B virus in vitro. In addition, our findings indicated that HLA-A11svE4 molecules were functional in activating CD8 + T cells through Ag presentation. Taken together, these results suggested that HLA-A11svE4 can homodimerize and form a novel heterodimeric complex with HLA-A11 open conformers. Furthermore, the data are consistent with HLA-A11svE4 playing a role in the immune escape of HIV-1.

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HLA-F and MHC Class I Open Conformers Are Ligands for NK Cell Ig-like Receptors

Cited by 120 publications

References 49 publications

Recognition of the Major Histocompatibility Complex (MHC) Class Ib Molecule H2-Q10 by the Natural Killer Cell Receptor Ly49C

Recognition of the Major Histocompatibility Complex (MHC) Class Ib Molecule H2-Q10 by the Natural Killer Cell Receptor Ly49C

Monoclonal antibodies to HLA‐E bind epitopes carried by unfolded β₂m‐free heavy chains

α3-Deletion Isoform of HLA-A11 Modulates Cytotoxicity of NK Cells: Correlations with HIV-1 Infection of Cells

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HLA-F and MHC Class I Open Conformers Are Ligands for NK Cell Ig-like Receptors

Cited by 120 publications

References 49 publications

Recognition of the Major Histocompatibility Complex (MHC) Class Ib Molecule H2-Q10 by the Natural Killer Cell Receptor Ly49C

Recognition of the Major Histocompatibility Complex (MHC) Class Ib Molecule H2-Q10 by the Natural Killer Cell Receptor Ly49C

Monoclonal antibodies to HLA‐E bind epitopes carried by unfolded β2m‐free heavy chains

α3-Deletion Isoform of HLA-A11 Modulates Cytotoxicity of NK Cells: Correlations with HIV-1 Infection of Cells

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Monoclonal antibodies to HLA‐E bind epitopes carried by unfolded β₂m‐free heavy chains