1. Introduction
Human leucocyte antigens (HLA) are highly specialized proteins, expressed on all nucleated cells and platelets, that form stable complexes with peptides of self or pathogenic proteins generated by proteasomal degradation. These peptide-HLA (pHLA) complexes are presented at the cell surface where they are subsequently recognized by T cells. Thus, T cells with their specific antigenic receptor (TCR) continuously scan an array of pHLA complexes which are presented on the cell surface [1]. One of the distinct properties of TCRs is that they can recognize an antigen only when it is associated with a host or “self”-encoded HLA molecule. This property of T cells was discovered by Zinkernagel and Doherty in 1974 and is called ´MHC-restriction´ [2]. The recognition of pHLA complexes by TCRs regulates many immunological responses such as antiviral cytolysis, graft or tumor rejection and regulation of B cell function. The genes encoding for HLA molecules are known to be the most polymorphic genes present in the whole genome. To date more than 9,000 HLA alleles have been identified of which there are ~7,300 HLA class I and ~2,200 class II polymorphic alleles (Figure 1) [3].
These polymorphisms do not occur throughout the HLA molecule, but are confined to specific AA positions in the peptide-binding region (PBR) [4, 5, 6]. They can cause alterations in the conformation of the PBR, thus changing the peptide binding specificities of these molecules [7]. The frequency of HLA alleles varies greatly among different ethnic groups. It has been postulated that evolutionary pressures such as those exerted by epidemics of infectious diseases might lead to the evolution of new HLA alleles having distinct peptide binding properties.
Following hematopoietic stem cell transplantation (HSCT), polymorphic differences between donor and recipient HLA class I molecules can lead to transplant rejection or graft-versus-host disease (GvHD). Extensive clinical data have demonstrated that the risk of GvHD strongly correlates with the number and kind of HLA mismatches and that both the type of amino acid (AA) substitution and its location within the HLA molecule can directly influence the transplantation outcome. Polymorphisms occurring within the PBR of HLA class I molecules determine which allogenic peptides are selectively bound and subsequently recognized as self or non-self by the effector T-lymphocytes that survey pHLA complexes on antigen presenting cells. Assembly of MHC class I heavy chain (hc) and β2 microglobulin (β2m) subunits with peptides is assisted by the peptide loading complex (PLC). Initially, proteasomally digested peptides are transported into the endoplasmic reticulum (ER) via the transporter associated with antigen processing (TAP) and are then loaded onto HLA class I molecules with the assistance of the PLC. The transmembrane glycoprotein tapasin (TPN) functions within this multimeric PLC as a disulfide-linked heterodimer along with the thiol oxidoreductase ERp57 to stabilize the empty class I molecule and promotes the selection of high affinity peptides. In addition to bridging HLA class I molecules with TAP, TPN was found to stabilize the peptide-receptive state of HLA class I molecules and increased the steady state levels of TAP heterodimers. Certain HLA class I polymorphisms within the PBR appear not only to influence the repertoire of bound peptides, but also determine the requirement for PLC mediated acquisition and optimal loading of peptides for the given HLA class I molecule. Whereas most class I allotypes associate strongly with the PLC and are highly dependent upon TPN for effective presentation of high affinity peptides and cell surface expression, others can acquire peptides even without assistance from the PLC but are then sub-optimally loaded. Due to the crucial role of TPN in selecting peptides, its indirect role in the immunorecognition of pathogens becomes obvious. This makes TPN an ideal target for viruses to interfere with the presentation of viral peptides to CTLs. For instance, US3 protein of HCMV binds to TPN and acts as a TPN inhibitor. This affects the antigen presentation by TPN-dependent HLA class I molecules. However, TPN-independent molecules can selectively escape the US3 mediated class I retention and continue to present the viral peptides.
Given HLA class I polymorphisms affect the generic antigen processing pathway and their dependency on TPN for antigen presentation. TPN-independency is occurring very rarely and might have evolved as an evolutionary trade-off to combat viral infections. However, presentation of unusual ligands by certain HLA class I alleles could be a risk factor during stem cell transplantation and needs to be considered during donor selection process. The future of HSCT relies on our understanding of how successful clinical outcomes can be achieved despite patient-donor allelic mismatches.
2. HLA polymorphisms and transplantation
The HLA system is one of the major barriers in hematopoietic stem cell transplantation (HSCT) and the degree of HLA matching is found to reflect on the outcome following transplantation. The best result following HSCT is achieved when an identical twin or a genotypically HLA identical sibling is used as donor. However, only 30 % of the donors for HSCT have a HLA identical sibling donor available [8]. Therefore, in most of the situations, HLA haplo-identical related, matched unrelated or partially matched related or unrelated donors are considered for transplantation. However, these transplants are associated with high risks of post-transplant complications such as graft failure/rejection or graft-versus-host disease (GvHD), mainly because of undefined or HLA incompatibilities. Many studies have demonstrated the negative impacts of HLA mismatches on the outcome following HSCT [9-11]. To understand the magnitude of distinct mismatches between HLA variants, several studies analyzed allele specific peptide motifs towards a rating of incompatibility [12-21] [22] [23, 24]. The knowledge of the peptide binding motifs of individual alleles and their comparison within allelic groups is the basis for understanding the impact of a given mismatch and is fundamental in predicting the relevance of allelic differences. Since allelic mismatches occurring at critical residues within the class I heavy chain may cause allorecognition, high resolution matching of patients and unrelated donors have been found to significantly improve post-transplant survival [25], lower the incidence and severity of GvHD [26, 27] and improve engraftment [28, 29]. The question whether a mismatch is permissive or not is critical in deciding which individual is the best matched donor. This could be achieved by conducting a systematic study to determine the effect of AA sequence polymorphisms on the function of a particular HLA molecule and on the immune responses post-transplantation.
3. HLA class I molecules and the peptide loading complex
HLA class I molecules loaded with high affinity peptides are essential for efficient immune surveillance and elimination of virally infected cells by CTLs. Newly synthesized class I hc and ß2m are translocated into the ER by their amino terminal signal sequences. Following translocation, HLA class I hcs are glycosylated and folded by the formation of two intra-chain disulphide bonds. Calnexin (CNX) facilitates the stabilization of class I hc and its association with ß2m. Following the formation of class I hc - ß2m heterodimer, CNX is replaced by calreticulin (CRT). Peptides are loaded onto the class I heterodimer by a complex machinery consisting of many chaperons, known as the peptide loading complex (PLC). The PLC consists of the transporter associated with antigen processing (TAP) heterodimers, transmembrane glycoprotein – TPN, lectin like chaperon – CRT, thiol oxidoreductase – Erp57 which is non-covalently associated with CRT and disulphide linked to TPN (Figure 2).
Peptides presented by HLA class I molecules originate mostly from cytosolic or nuclear proteins and are processed by the proteasome, a multicatalytic protease complex. TAP helps in the translocation of peptides from cytosol into the ER lumen. TPN bridges class I - ß2m heterodimer to TAP and acts as a peptide editor, facilitating the loading of high affinity peptides onto HLA class I molecules. Stable HLA class I molecules dissociate from TAP heterodimers and are transported through the golgi complex to the cell surface where they present peptides to CD8+ T cells.
4. Tapasin
TPN is a type 1 transmembrane glycoprotein, 428 amino acid long and consisting of three parts: an N-terminal ER luminal region consisting of two domains, a transmembrane domain and a short cytoplasmic tail. TPN has multitudinous roles within the PLC, all of which are directed towards peptide presentation by the class I molecules. The transmembrane domain of TPN interacts with TAP and bridges TAP to class I molecules. TPN facilitates the stabilization of TAP and promotes the binding and translocation of peptides by TAP. Absence of TPN abrogates the binding of class I molecules to TAP. It was also shown that certain class I molecules presented at the cell surface in the absence/independent of TPN were very unstable and dissociated rapidly. The double lysine motif at the C-terminus of the TPN molecule mediates its interaction with coat protein type I (COP I) vesicle and facilitates the recycling of class I molecules which have not been not loaded with optimal peptides. Mutational analysis identified a conserved region on the ER-luminal domain of TPN that interacts with HLA class I molecules and was found to be critical for peptide loading and its editing function. Polymorphisms occurring in HLA class I molecules are found to affect the dependency of these molecules on TPN for antigen presentation and cell surface expression.
5. Inhibitors of TPN
TPN is a critical component of the PLC which plays an important role in optimization and selection of peptides subsequently presented on the cell surface by HLA class I molecules [30, 31]. Transmembrane glycoprotein US3 expressed during the immediate early phase of HCMV infection binds to TPN and inhibits its ability to load kinetically stable peptides onto HLA class I molecules, thus retaining class I molecules in the ER [32]. However, not all HLA class I molecules are equally affected by US3, thus highlighting that not all HLA class I molecules are equally dependent upon TPN for maturation in the ER [33]. US3 and TPN are associated by their ER luminal domains, but the transmembrane domains are also required for the inhibition of TPN [32]. Another transmembrane glycoprotein E3-19K from the adenovirus also inhibits crucial functioning of TPN by blocking its ability to bridge TAP to HLA class I molecules. E3-19K associates with TAP and impairs the formation of TAP-TPN complex and inclusion of TAP in the PLC [34]. This competitive inhibition by E3-19K delays the maturation and assembly of TPN-dependent HLA class I loading complex [34].
Certain other viral proteins prevent surface expression of HLA class I molecules by retention or degradation of HLA molecules in the ER. For example, cowpox virus protein 203 (CPXV 203] causes retention of HLA class I molecules in the ER [35]. US2 and US11 proteins from HCMV and mK3 protein from mouse herpes virus directs HLA class I molecules towards proteasomal degradation [36] [37] [38] [39]. Sorters such as HIV-1 protein Nef and murine CMV protein gp48 averts the trafficking of HLA class I molecules from golgi to lysosomal compartment where they are subsequently degraded [40] [41] [42].
6. Interactions between HLA class I molecules and TPN
In addition to bridging HLA class I molecules to TAP, TPN was found to stabilize the peptide-receptive state of class I molecules [43] and increase the steady state levels of TAP heterodimers [44]. TPN also facilitated the retention of empty class I molecules in the ER of insect cells [30]. Barnden
7. Peptide editing function of TPN
Many studies have highlighted the role of TPN in stabilizing HLA class I molecules [30, 31, 45, 55] and maintaining them in a peptide-receptive conformation [56]. It has also been shown that TPN facilitates peptide optimization, a process in which bound peptides of low affinity are exchanged for the high affinity ones [45, 57-61]. These functions were attributed to TPN based on the findings that the class I-peptide complexes expressed on the surface of cells lacking TPN were less stable than those complexes expressed on normal cells containing TPN. However, analysis of peptides eluted from HLA class I complexes expressed on the cell surface in the presence and absence of TPN demonstrated no co-relation between the decreased stability of HLA class I-peptide complexes and binding of low-affinity peptides in TPN deficient cells [62]. The authors suggested that the plausible ability of TPN to stabilize immature HLA class I molecules in the ER instead broadens the bound peptide repertoire both in terms of complexity of bound peptides and their binding affinities [62]. A more recent study conducted by Howarth
Many groups have established
8. TPN dependence/ independence of HLA class I molecules
Polymorphisms occurring at specific AA positions within the HLA class I hc are found to influence the dependency of these molecules on TPN for efficient cell surface expression and peptide presentation. It has been hypothesized that the nature of AAs occurring at the bottom of the F pocket influences the conformational flexibility of empty class I molecules [55, 64], which could in turn determine the ability of a particular allotype to bind peptides in the presence or absence of TPN [65]. It has been shown that in the TPN dependent alloforms, the region around the F pocket of the peptide binding groove is in a disordered conformation due to a partially open disulphide bond in the α2 domain [66] and that TPN facilitates the conversion of this disordered conformation into a stable, peptide-receptive conformation [55].
Studies performed using TPN deficient cell lines (LCL 721.220] transfected with various HLA-A and B allotypes demonstrated an altered dependency of these class I variants on TPN for their cell surface expression [33, 67, 68] [18]. HLA-B*27:05 molecules showed high levels of surface expression and were able to present specific viral peptides even in the absence of TPN. On contrary, HLA-B*44:02 molecules were found to be highly dependent upon TPN for these functions and HLA-B8 molecules showed intermediate dependency on TPN [33]. It has also been observed that while HLA-A1 molecules fail to present antigens in the absence of TPN [31], HLA-A2 molecules present peptides very efficiently on the surface of these cells [69].
Many studies have highlighted the importance of AAs occurring at position 114 of class I hc in determining their dependency on TPN for efficient antigen processing and presentation [33, 55, 64, 70, 71]. Park
Some of the more recent studies have shed light on the functional consequences of HLA class I polymorphisms in modulating the presented peptide repertoire. It could be demonstrated that the TPN dependent B*44:02116Asp and TPN-independent variant B*44:05116Tyr differed in their preference at the PΩ anchor residue [64]. Binding preference of HLA-B*44:05 at P9 was restricted to Phe while B*44:02 showed preference for both Phe and Tyr at this position, largely due to the ability of Asp116 in B*44:02 to make hydrogen bond with Tyr at P9 [64]. In yet another study, it was demonstrated that although the surface expression of HLA-B*27:05 was similar both in the presence and absence of TPN, there was a difference in the cytotoxic lysis of B*27:05 targets upon infection with recombinant vaccina viruses under these two circumstances. Measurement of cytotoxicity at four hours post infection demonstrated that the lysis of B*27:05/TPN negative targets was only half the cytotoxicity level observed for B*27:05/TPN positive target cells. At 12 hours post infection, the cytotoxic lysis of B*27:05/TPN negative targets was similar to B*27:05/TPN positive target cells. However, this study pointed out an impairment in the presentation of specific viral peptides by B*27:05 in the absence of TPN. Although there was some overlap in the peptides presented in the presence and absence of TPN, unique set of peptides were selected and presented by B*27:05 under these two conditions. B*27:05 molecules on the surface of cells lacking TPN are more unstable probably owing to the nature of peptides selected and bound by them in the absence of TPN [33].
Studies examining single AA exchanges within the hc of naturally occurring HLA class I alleles have identified some of the residues in the α2 domain which are of critical importance for the interaction of class I molecules with the PLC components. Elliott
Previous studies have demonstrated that the nature of AAs occurring at residues 114 or 116 determine the interaction of these different class I allotypes with the PLC components [64]. These two residues are located in the F pocket of the PBR, that interacts with the C-terminal peptide residue and thus determine the nature of a bound peptide. It is found that certain AA polymorphisms occurring at these positions result in loading and presentation of peptides independent of the loading complex (TAP/ TPN) [64, 71] via a non-classical pathway resulting in the presentation of pHLA complexes, that might be poorly tolerated by the self immune system.
9. Impact of mismatch at residue 156 in B*44 allotypes
Recently the association of TPN with HLA subtypes featuring micro-polymorphisms at AA position 156 was discovered [18]. This position is part of the pockets D and E within the peptide binding region and contacts peptide of canonical length at positions p3 and p7 [75], explaining its distinct structural role in influencing the conformation of the pHLA complex [76] [77]. Polymorphisms at residue 156 represent one of the most non-permissive transplantation scenarios and are associated with acute GvHD for HLA-A, -B and -C alleles [58] [78] [76] [77] [79] [80].
The HLA-B*44 allelic group occurring in approximately 25 % of the Caucasian population has four naturally occurring variants (B*44:02156Asp, 44:03156Leu, 44:28156Arg, 44:35156Glu), which exclusively differ by just one single AA at residue 156. The mismatch B*44:02156Asp / B*44:03156Leu e.g. is described to represent a non-permissive transplantation scenario. The association with strong alloreactive T-cell responses due to distinct structural differences between B*44:02 and B*44:03 pHLA complexes leads to acute GvHD [79]. It has also been demonstrated that the resulting mismatch leads to a disparity in the derived peptide repertoire, which explains the cytotoxic T-lymphocyte recognition of different pHLA landscapes between B*44:02 and B*44:03. Structural involvement of position 156 in influencing the conformation of PBR was demonstrated by comparing the crystal structures of HLA-B*44:02 and HLA-B*44:03 complexed with the same, natural high affinity ligand [18]. In order to determine if position 156 is also involved in the PLC/HLA association and if polymorphism at this position affect TPN dependency through alteration of the structure and property of the PBR and subsequently the peptide repertoire, we investigated the mode of peptide loading for the B*44/156 mismatched variants.
Our data demonstrates that exclusively HLA-B*44:28156Arg variant can acquire peptides independently of TPN and that AA position 156 is unambiguously responsible for the HLA/TPN interaction within B*44 subtypes. Based on its position and orientation, residue 156 is unlikely to contact TPN directly. Similarly, TPN-dependent B*44:02 and TPN-independent B*44:05 alleles with a micropolymorphic difference at residue 116 also appear unlikely to contact TPN directly. Although AA residue 156 is not a part of the first segment of α2-helix, it is likely that it influences the strand/loop region that TPN interacts with and in a similar manner to residue 116 affects the stability/dynamics of the unloaded HLA molecule.
By systematically analysing the influence of residue 156 in B*44 variants and their interaction with TPN could clearly be demonstrated. Using mass spectrometry we sequenced those peptides derived from B*44:02 aquired with the assistance of TPN and hence through the optimization machinery of the PLC and compared those with peptides bound to B*44:28 aquired in a TPN-independent manner. Significant differences between these sets of peptides could be observed, both in their attributed binding affinity and in the length of the derived peptides. The peptide repertoires of sHLA-B*44:02 and sHLA-B*44:28 display subtle differences, suggesting an alternate antigen presentation pathway, the core binding motifs are strongly retained [18]. The results from the structural insight through computational analysis indicated a role for 156Arg in increasing the stability of the pHLA complex through contacts to both Asp114 and to peptide backbone at P5 (Figure 3).
Our results indicate that the HLA-B*44:28156Arg variant stabilises the binding groove in its empty state, thus negating the contribution of the PLC and allowing independent loading of high affinity peptides. The interaction between Arg156 and Asp114 on the floor of the peptide binding groove seems to be able to generate a stable peptide receptive state.
10. Conclusion
TPN independency offers flexibility on one hand, because it provides an effective pathogen evasion, however peptides are loaded suboptimally and that might influence the immunogenicity and half-life time of pHLA complexes and this might result in autoimmunity.
The question whether TPN-dependency or TPN-independency is advantageous or not is likely to depend on the combination of HLA-A, -B, and C- alleles of an individual. An appreciation of the interaction between TPN, HLA class I molecules and peptide loading may therefore be important not only during viral infections, but also while considering transplantation scenarios.
Nomenclature
Human leucocyte antigens (HLA)
Major Histocompatibility Complex (MHC)
T cell receptor (TCR)
peptide-HLA complexes (pHLA)
peptide-binding region (PBR)
hematopoietic stem cell transplantation (HSCT)
graft-versus-host disease (GvHD)
amino acid (AA)
heavy chain (hc)
β2 microglobulin (β2m)
peptide loading complex (PLC)
endoplasmic reticulum (ER)
transporter associated with antigen processing (TAP)
tapasin (TPN)
cytotoxic T lymphocyte (CTL)
human cytomegalie virus (HCMV)
Calnexin (CNX)
Calreticulin (CRT)
Acknowledgments
The authors would like to thank Heike Kunze-Schumacher for excellent technical assistance.
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