HLA-F: A New Kid Licensed for Peptide Presentation Article in - - PDF document

See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/317724441

HLA-F: A New Kid Licensed for Peptide Presentation

Article in Immunity · June 2017

DOI: 10.1016/j.immuni.2017.06.004

CITATIONS

5

READS

71

2 authors, including: Some of the authors of this publication are also working on these related projects: Regulation of KIR binding by HLA-I bound peptides View project T cell recognition of public neoantigens View project Malcolm J. W. Sim National Institutes of Health

23 PUBLICATIONS 129 CITATIONS

SEE PROFILE

All content following this page was uploaded by Malcolm J. W. Sim on 29 October 2018.

The user has requested enhancement of the downloaded file.

cellular miRNAs, rather than loss of siRNA

• production. I would therefore argue that

a definitive answer to the question of whether RNAi serves as a physiologically relevant antiviral innate immune response in mammals has not yet been obtained.

REFERENCES Benitez, A.A., Spanko, L.A., Bouhaddou, M., Sachs, D., and tenOever, B.R. (2015). Cell Rep. 13, 1456–1466. Bogerd, H.P., Skalsky, R.L., Kennedy, E.M., Fur- use, Y., Whisnant, A.W., Flores, O., Schultz, K.L., Putnam, N., Barrows, N.J., Sherry, B., et al. (2014). J. Virol. 88, 8065–8076. Bucher, E., Hemmes, H., de Haan, P., Goldbach, R., and Prins, M. (2004). J. Gen. Virol. 85, 983–991. Cullen, B.R., Cherry, S., and tenOever, B.R. (2013). Cell Host Microbe 14, 374–378. Garcia-Sastre, A., Egorov, A., Matassov, D., Brandt, S., Levy, D.E., Durbin, J.E., Palese, P., and Muster, T. (1998). Virology 252, 324–330. Kennedy, E.M., Whisnant, A.W., Kornepati, A.V., Marshall, J.B., Bogerd, H.P., and Cullen, B.R. (2015). Proc. Natl. Acad. Sci. USA 112, E6945–E6954. Li, Y., Basavappa, M., Lu, J., Dong, S., Cronkite, D.A., Prior, J.T., Reinecker, H.C., Hertzog, P., Han, Y., Li, W.X., et al. (2016). Nat. Microbiol. 2, 16250. Maillard, P.V., Van der Veen, A.G., Deddouche- Grass, S., Rogers, N.C., Merits, A., and Reis, E.S.C. (2016). EMBO J. 35, 2505–2518. Parameswaran, P., Sklan, E., Wilkins, C., Burgon, T., Samuel, M.A., Lu, R., Ansel, K.M., Heissmeyer, V., Einav, S., Jackson, W., et al. (2010). PLoS

• Pathog. 6, e1000764.

Qiu, Y., Xu, Y., Zhang, Y., Zhou, H., Deng, Y.-Q., Li, X.-F., Miao, M., Zang, Q., Zhong, B., Hu, Y., et al. (2017). Immunity 46, this issue, 992–1004.

HLA-F: A New Kid Licensed for Peptide Presentation

Malcolm J.W. Sim1 and Peter D. Sun1,*

1Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, 12441 Parklawn Drive, Rockville, MD 20852, USA

*Correspondence: psun@nih.gov http://dx.doi.org/10.1016/j.immuni.2017.06.004

HLA-F, a non-classical MHC molecule, is not known to present peptides. Dulberger et al. (2017) show that HLA-F contains a distinct peptide-binding groove and can present a diverse array of peptides. LIR1, however, recognized HLA-F away from bound peptide, leaving open whether peptide-HLA-F-specific T and NK receptors exist.

MHC class I (MHC-I) molecules play multiple important roles in both innate and adaptive immune responses. Im- mune cells survey cellular health through interactions with MHC-I via presentation

• f peptide antigen derived from intra-

cellular sources. MHC-I molecules— both classical (MHC-Ia) and non-classical (MHC-Ib)—have common structural fea- tures that allow for this function, specif- ically a peptide binding cleft composed

• f the a1 and a2 domains, stabilized

through associations with b2 microglobu- lin (b2M). Human MHC-Ia molecules— HLA-A, HLA-B, and HLA-C—are highly polymorphic, expressed on all nucleated cells, and are the principle ligands for T cell receptors (TCR) and killer-cell immunoglobulin-like receptors (KIR). Hu- man MHC-Ib molecules—HLA-E, HLA-F, and HLA-G—have limited polymorphism and non-uniform tissue distribution and are largely ligands for innate immune re- ceptors (Parham and Moffett, 2013). HLA-E and HLA-G have relatively well- defined roles in immunity. HLA-E pre- sents peptides derived from the leader sequences of other MHC-I molecules and is recognized by the innate immune receptor CD94:NKG2A, expressed pre- dominantly on natural killer (NK) cells. HLA-G is a ligand for LIR1 (also known as ILT2 or LILRB1) and KIR2DL4 and thought to act primarily at the maternal- fetal interface (Parham and Moffett, 2013). However, HLA-F appears not to fit this pattern and decades of work have left unanswered the central question as to whether HLA-F presents peptide anti- gen for immune surveillance. In this issue

• f

Immunity, Dulberger et al. (2017) demonstrate that HLA-F can present pep- tide antigen by solving the first crystal structures of HLA-F. They characterize the peptide repertoires derived from HLA-F and present structural evidence for HLA-F recognition by LIR1. Attempts to find HLA-F associated with b2M and sequence peptides from HLA-F have been largely unsuccessful (Good- ridge et al., 2010). Indeed, a growing body of evidence suggest that HLA-F exists as an open conformer (OC) devoid

• f peptide and b2M, which functions as

a ligand for NK cell receptors such as KIR3DS1 (Garcia-Beltran et al., 2016; Goodridge et al., 2013). Although there is indication that HLA-F interacts with b2M in cell lines, structural evidence for this as- sociation is lacking (Lee and Geraghty, 2003). To circumvent this problem and generate large quantities of HLA-F-b2M complex sufficient for structural analysis, the authors engineered b2M to HLA-F as a single polypeptide chain for production in insect cells (Dulberger et al., 2017). The X-ray crystal structure of this protein revealed a canonical class I MHC fold, with very little deviation from HLA-A2 or HLA-G. Similarly, the peptide-binding groove was open, akin to peptide-loaded molecules, not molecules with related MHC folds devoid of peptide like FcRn

• r MICA. Evoking the classical study by

Bjorkman and Wiley (Bjorkman et al., 1987), there was a region of electron den- sity within the peptide binding groove, unaccounted for by HLA-F or b2M. This

Immunity

Previews

972 Immunity 46, June 20, 2017 Published by Elsevier Inc.

extra density could be modeled as a pep- tide of 8 amino acids long, confirming HLA-F as a peptide presentation mole-

• cule. Given the cellular origin of HLA-F,

the electron density in the structure likely derives from multiple peptide sequences precluding understanding how HLA-F presents a given peptide sequence, but does allow for the general features of how HLA-F presents peptides to be

• deduced. Previous studies on MHC-Ia

and MHC-Ib have established that pep- tides of 8–11 amino acids are presented using anchor residues near both termini

• f the peptide. However, the N-terminal

anchor pocket (termed A pocket) is blocked in HLA-F due to W62, a substitu- tion from Arg that arose recently between chimpanzee and human. This causes the peptide N terminus to ‘‘snake up and out

• f the groove’’ and instead, HLA-F an-

chors the peptide in the center and at its C terminus. Further, using mass spec- trometry, Dulberger et al. (2017) showed that HLA-F bound a diverse number

• f peptides (>2,000), many more than

those bound to HLA-E (Goodridge et al., 2010). These peptides had no recogniz- able sequence patterns except the presence of charged Asp, Arg, or Lys at their C termini and also had consider- able diversity in length ranging from 7 to 30+ amino acids long. Thus, HLA-F presents peptides that break the tradi- tional length constraints associated with MHC-I molecules by N-terminal exten- sions out of the groove. Additionally, HLA-F peptides had a high level of post-translational modifications such as phosphorylation. The ability to bind diverse peptides begs the question of antigen presentation by HLA-F. The authors demonstrated here that the LIR1 receptor recognized peptide-bound but not the OC form of HLA-F with 2 mM affinity. LIR1 has previ-

• usly been shown to bind with MHC-Ia

and MHC-Ib molecules but binds more tightly to a viral MHC-homolog UL18. Dulberger et al. (2017) further solved the complex crystal structure of LIR1- bound HLA-F (Figure 1). The X-ray struc- ture showed that LIR1 recognized the underside of HLA-F involving b2M and the a3 regions, like that of UL18 (Fig- ure 1). However, LIR1 recognition of HLA-F, though it depends on b2M, ap- pears to lack peptide specificity, as the W62R substitution, which significantly reduced the HLA-F-bound peptide reper- toire in both diversity and number, only marginally altered LIR1 binding affinity. Since the LIR1 binding site is outside of the peptide binding groove of HLA-F, it doesn’t probe peptide sequence directly, leaving open the question of whether HLA-F, with its diverse peptides, can be recognized by other immune receptors that do such as TCRs or KIRs (Figure 1). Members of the KIR family are known to bind peptide-MHC in similar orientation as TCR and thus exhibit significant pep- tide selectivity (Boyington et al., 2000; Parham and Moffett, 2013; Sim et al., 2017). KIR are also recently evolved and differ between human and chimpanzee (Parham and Moffett, 2013). Thus, are there HLA-F-restricted TCRs or pep- tide sequence-dependent HLA-F-specific KIRs? Indeed, HLA-F tetramers stained PBMCs with a broader binding profile than that due to LIR1 expression alone. An equally intriguing issue is the func- tion of HLA-F OCs, which was shown previously to bind KIR3DS1, KIR3DL2, and KIR2DS4 (Garcia-Beltran et al., 2016; Goodridge et al., 2013). Using re- porter cell lines expressing KIR3DS1, KIR3DL2, KIR2DS4, and KIR2DL3, the authors confirmed previous observations except for KIR2DS4 (Figure 1). Interest- ingly, tetramers prepared from mamma- lian cell-expressed HLA-F exhibited similar but not identical PBMC binding profiles as HLA-F OCs, leaving open a tantalizing possibility of the existence of receptors that can differentiate between different forms of HLA-F and HLA-F com- plex with different peptide sequences. Through combined structural and pro- teomic studies, Dulberger et al. (2017) have greatly advanced our understanding in HLA-F and its diverse peptide reper-

• toire. It is quite possible that our current

knowledge of HLA-F is only the tip of the

• iceberg. Clear roles for HLA-F in biology

are emerging. HLA-F OCs are ligands for KIR3DS1 and expressed on HIV-infected CD4+ T cells (Garcia-Beltran et al., 2016). HLA-F is also expressed on extra- villous trophoblasts, placental derived cells essential for establishing spiral ar- teries that supply the fetus and placenta with maternal blood (Hackmon et al., 2017; Parham and Moffett, 2013). Given that MHC-I molecules and innate immune receptors are known to regulate preg- nancy in humans (Parham and Moffett, 2013), it is interesting to speculate that the R62W substitution that allows HLA-F to present its diverse peptide repertoire was selected for some benefit to human

• pregnancy. The fact that HLA-F exists in

two forms, both OC and in complex with peptide, raises the possibility that cell sur- face regulation of these two forms could have dramatic impacts on immune recep- tor recognition. A potential caveat of this work is that HLA-F and b2M were engi- neered together as single polypeptide chain, thus leaving unknown whether natural HLA-F, non-covalently associ- ated with b2M, behaves similarly. Never- theless, the findings presented here suggest that HLA-F with its recently

Figure 1. HLA-F Interacts with Immune Receptors in Both Peptide-Bound and Open Conformations Left: A summary of interactions currently known to involve either the open conformer or b2M and peptide- complexed HLA-F (shown in blue ovals) and various KIR (orange ovals), LIR1 (green ovals). Potential new HLA-F binding KIR and TCR are shown in red and pink, respectively. Right: Enlarged view of the center highlighted region showing both the crystal structure of LIR1 (shown in green) with peptide-bound HLA-F (in blue ribbons) by Dulberger et al. (2017) (PDB: 5KNM) and a potential interaction with KIR involving peptide, modeled from the structure of HLA-C*03:04 & KIR2DL2 complex by Boyington et al. (2000) (PDB: IEFX).

Immunity

Previews

Immunity 46, June 20, 2017 973

acquired peptide-binding ability indeed is the new kid in an extended family

• f MHC-I molecules proficient in anti-

gen presentation. It opens exciting new avenues for HLA-F with involvement in immune surveillance and the potential existence of peptide-sequence specific HLA-F restricted receptors. And the search is on.

REFERENCES Bjorkman, P.J., Saper, M.A., Samraoui, B., Ben- nett, W.S., Strominger, J.L., and Wiley, D.C. (1987). Nature 329, 506–512. Boyington, J.C., Motyka, S.A., Schuck, P., Brooks, A.G., and Sun, P.D. (2000). Nature 405, 537–543. Dulberger, C.L., McMurtrey, C.P., Ho ¨ lzemer, A., Neu, K.E., Liu, V., Steinbach, A.M., Garcia-Beltran, W.F., Sulak, M., Jabri, B., Lynch, V.J., et al. (2017). Immunity 46, this issue, 1018–1029. Garcia-Beltran, W.F., Ho ¨ lzemer, A., Martrus, G., Chung, A.W., Pacheco, Y., Simoneau, C.R., Rucevic, M., Lamothe-Molina, P.A., Pertel, T., Kim, T.E., et al. (2016). Nat. Immunol. 17, 1067–1074. Goodridge, J.P., Burian, A., Lee, N., and Geraghty, D.E. (2010). J. Immunol. 184, 6199–6208. Goodridge, J.P., Burian, A., Lee, N., and Geraghty, D.E. (2013). J. Immunol. 191, 3553–3562. Hackmon, R., Pinnaduwage, L., Zhang, J., Lye, S.J., Geraghty, D.E., and Dunk, C.E. (2017). Am.

• J. Reprod. Immunol. 77, e12643.

Lee, N., and Geraghty, D.E. (2003). J. Immunol. 171, 5264–5271. Parham, P., and Moffett, A. (2013). Nat. Rev.

• Immunol. 13, 133–144.

Sim, M.J., Malaker, S.A., Khan, A., Stowell, J.M., Shabanowitz, J., Peterson, M.E., Rajagopalan, S., Hunt, D.F., Altmann, D.M., Long, E.O., and Boyton, R.J. (2017). Front. Immunol. 8, 193.

The TORC that Gets the GC Cycling

Elissa K. Deenick1,2,* and Stuart G. Tangye1,2

1Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia

• 2St. Vincent’s Clinical School, University of New South Wales, Darlinghurst, NSW, Australia

*Correspondence: e.deenick@garvan.org.au http://dx.doi.org/10.1016/j.immuni.2017.06.003

The signaling pathways regulating positive selection in germinal centers (GCs) are incompletely understood. Ersching et al. (2017) identify a critical but temporal role for the action of the kinase mechanistic target of rapamycin complex (mTORC1), which promotes key changes in GC B cells and thereby facilitates affinity maturation.

Naive B cells differentiate into memory B cells and plasma cells in response to T-dependent antigens within germinal centers (GCs), transient structures located in the follicles

• f secondary

lymphoid tissues. GCs are the site of pro- liferation, somatic hypermutation, and se- lection of high-affinity Ag-specific B cells. However, these processes take place in defined regions of the GC; proliferation and somatic hypermutation dominate the dark zone (DZ), and affinity-based selection occurrs in the light zone (LZ) (Mesin et al., 2016). A GC reaction is not a one-way street—appropriate GC re- sponses involve the cyclic re-entry of B cells between the LZ and the DZ (Figure 1). Indeed, positive selection of high-affinity B cells occurs in the LZ as a result of their ability to outcompete low- affinity B cells for antigens and help pro- vided by specialized CD4+ T cells termed T follicular helper (Tfh) cells, which pro- vide the signals that initiate proliferation and migration back into the DZ, where the cycle begins again (Mesin et al., 2016). A GC reaction is a classic scenario of survival of the fittest. Consequently, to sur- vive a GC reaction, activated B cells must alter their physiology and metabolism. Thus, defining exact signals controlling B cell selection, survival, expansion, and trafficking is key to understanding the regulation of GC responses and how this can go awry, whereupon it leads to dysre- gulated B cell responses that potentially manifest as production of autoantibodies

• r B cell malignancy. Previous work

identified a number of factors critical for these processes; such factors include the cell-cycle regulator and proto-oncogene c-Myc, which initiates the cell cycle in the LZ (Calado et al., 2012; Dominguez-Sola et al., 2012), and the transcription factor AP4, which allows multiple rounds of divi- sion in the DZ (Chou et al., 2016)(Figure 1). However, positive selection and expan- sion of high-affinity B cells within the GC requires a multitude of signals, the com- plex temporal regulation of which remains incompletely defined. Several studies have previously utilized a system that artificially promotes positive selection of B cells in the LZ by using an antibody directed against the surface re- ceptor DEC205 linked to the antigen oval- bumin (DEC-OVA). This enables delivery

• f antigen to the B cells, resulting in pre-

sentation by the B cells and promoting in- teractions between B cells and Tfh cells, which then drive the migration and prolif- eration of these B cells into the DZ. Using this system, researchers have shown that the extent of proliferation in the DZ was proportional to the amount of help pro- vided by Tfh cells (reviewed in [Mesin et al., 2016]). In this issue of Immunity, Ersching et al. have used this system to identify additional signaling pathways that might underpin the complex processes of a GC reaction (Ersching et al., 2017). Genes

Immunity

Previews

974 Immunity 46, June 20, 2017 ª 2017 Elsevier Inc.

View publication stats View publication stats