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MHC I assembly and peptide editing — chaperones,clients, and molecular plasticity in immunityChristoph Thomas and Robert Tampe
Available online at www.sciencedirect.com
ScienceDirect
Peptides presented on MHC I molecules allow the immune
system to detect diseased cells. The displayed peptides
typically stem from proteasomal degradation of cytoplasmic
proteins and are translocated into the ER lumen where they are
trimmed and loaded onto MHC I. Peptide translocation is
carried out by the transporter associated with antigen
processing, which forms the central building block of a
dynamic assembly called the peptide-loading complex (PLC).
By coordinating peptide transfer with MHC I loading and
peptide optimization, the PLC is a linchpin in the adaptive
immune system. Peptide loading and optimization is catalyzed
by the PLC component tapasin and the PLC-independent
TAPBPR, two MHC I-dedicated enzymes chaperoning empty
or suboptimally loaded MHC I and selecting stable peptide-
MHC I complexes in a process called peptide editing or
proofreading. Recent structural and functional studies of
peptide editing have dramatically improved our understanding
of this pivotal event in antigen processing/presentation. This
review is dedicated to Vincenzo Cerundolo (1959–2020) for his
pioneering work in the field of antigen processing/presentation.
Address
Institute of Biochemistry, Biocenter, Goethe University Frankfurt,
Max-von-Laue Str. 9, Frankfurt, 60438 Main, Germany
Corresponding authors:
Thomas, Christoph ([email protected]),
Tampe, Robert ([email protected])
Current Opinion in Immunology 2021, 70:48–56
This review comes from a themed issue on Antigen processing
Edited by Scheherazade Sadegh-Nasseri
https://doi.org/10.1016/j.coi.2021.02.004
0952-7915/ã 2021 Elsevier Ltd. All rights reserved.
IntroductionNucleated cells of jawed vertebrates employ peptide-
MHC I (pMHC I) complexes on their surface to alert
the immune system about intracellular and extracellular
changes caused by pathogenic infection or malignant
transformation. Peptides bound to MHC I are recognized
by T-cell receptors (TCRs) on CD8+ (cytotoxic) T cells
and by natural killer (NK) cell receptors, allowing the
immune system to mount appropriate responses against
Current Opinion in Immunology 2021, 70:48–56
compromised cells without harming healthy cells [1,2].
The peptides displayed on MHC I are typically gener-
ated by proteasomal degradation of cytosolic proteins and
defective ribosomal products (DRiPs) and include even
spliced and post-translationally modified peptides [3].
The heterodimeric ATP-binding cassette (ABC) trans-
porter TAP1/2 (ABCB2/B3), which forms the cornerstone
of a dynamic, supramolecular assembly called the PLC,
selectively transports a small fraction of these peptides
into the ER where they can be trimmed by aminopepti-
dases such as ERAP1/2 to a length of 8–10 amino acids
that is optimal for fitting into the MHC I groove [4–6]
(Figure 1). In the ER, the peptides are loaded onto MHC
I complexes, which are heterodimers of an N-glycosy-lated, highly polymorphic heavy chain and the invariant
light chain b2-microglobulin (b2m). The loading of pep-
tides onto MHC I is catalyzed and subject to quality
control mechanisms: the MHC I-specific chaperones
tapasin (Tsn), a key component of the PLC, and
TAPBPR, a Tsn homolog that operates outside the
PLC, stabilize intrinsically unstable unliganded MHC I
complexes and function as peptide-exchange catalysts,
discriminating against pMHC I complexes that carry low-
affinity peptides [7–16] (Figure 1). By accelerating the
dissociation of suboptimal peptides, Tsn and TAPBPR
are also expected to facilitate peptide trimming by
ERAP1/2. Properly folded and kinetically stable pMHC
I complexes are eventually able to egress from the ER via
the Golgi compartment to the cell surface where they are
scanned by TCRs of cytotoxic T lymphocytes and by
killer cell immunoglobulin-like receptors (KIRs) of NK
cells [17] (Figure 1). It is important to note that peptide
editing by Tsn and TAPBPR is of crucial importance for
immunosurveillance, as it generates a repertoire of
pMHC I complexes that are stable enough to be scruti-
nized by immune cells and prevents the display of low-
affinity epitopes that would be exchanged for extracellu-
lar peptides and lead to a misrepresentation of the cellular
health status.
Besides the two pMHC I quality inspectors Tsn and
TAPBPR, several additional chaperones and folding
assistants shepherd MHC I molecules on their way from
translational birth to their final destination, the cell sur-
face: After the core N-glycan Glc3Man9GlcNAc2 is co-
translationally transferred to a conserved asparagine in the
MHC I heavy chain by oligosaccharyltransferase (OST)
and the outer two glucose residues are subsequently
cleaved off by glucosidase I and II, the resulting mono-
glucosylated dodecasaccharide is recognized by the
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MHC I chaperones in antigen processing Thomas and Tampe 49
Figure 1
Current Opinion in Immunology
Assembly and quality control of MHC I molecules and complexes. MHC I complexes are recruited to the PLC by the scaffolding chaperone
calreticulin (step 1) where the MHC I-dedicated chaperone tapasin stabilizes empty and suboptimally loaded MHC I complexes and facilitates
loading of high-affinity peptides in a peptide-rich environment generated by the ABC transporter TAP1/2 (step 2). The peptide-rich environment of
the PLC that tapasin is operating in is depicted by a red cloud. The tapasin homolog TAPBPR represents a second pMHC I quality inspector,
which accelerates peptide loading outside the PLC (step 3). In addition, TAPBPR aids the folding sensor and glucosyltransferase UGGT1 in
detecting and re-glucosylating peptide-deficient MHC I (step 4). This enables the mono-glucosylated MHC I to re-engage calnexin/calreticulin and
to (re-)visit the PLC in order to capture a suitable peptide (step 5). Stably loaded pMHC I complexes can leave the ER and migrate via the Golgi
compartment to the cell surface (step 6) where they are scanned by cytotoxic T cells (step 7) and natural killer cells (step 8).
scaffolding lectin chaperone calnexin (Cnx), which
recruits the thiol oxidoreductase ERp57 [18,19]
(Figure 1). In general, ERp57 supports folding of glyco-
proteins by facilitating disulfide bond isomerization. After
binding of b2m and dissociation of Cnx, the inherently
labile empty MHC I is escorted by calreticulin (Crt), the
soluble homolog of Cnx. In the next step, Tsn-dependent
allomorphs assemble together with Crt, Tsn-ERp57, and
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TAP into the PLC, with TAP1/2 forming the central
assembly platform [1,20] (Figure 1). Through its action as
a peptide transporter with pronounced substrate specific-
ity, TAP creates an environment that is characterized by a
high local concentration of peptides suitable for Tsn-
catalyzed MHC I loading within the PLC. Important
insights into the conformational dynamics of the antigen
translocation complex within the PLC have been gained
Current Opinion in Immunology 2021, 70:48–56
50 Antigen processing
by investigating the bacterial ABC transporter TmrAB,
which can serve as a model system for TAP, as the two
transporters share structural as well as functional homol-
ogy [21]. Recently, nine different high-resolution cryo-
EM structures allowed us to dissect the full conformation
cycle of TmrAB. In conjunction with single-turnover
studies that delineated the power stroke of substrate
transport, these structures substantially enhanced our
mechanistic understanding of peptide-translocating
molecular machines [22��,23�]. Those pMHC I com-
plexes, which are properly folded and charged with a
high-affinity cargo when their remaining glucose moiety
is removed by glucosidase II, are licensed to exit the ER
and travel through the Golgi apparatus to the cell surface
(Figure 1).
In addition to Tsn, TAPBPR operates downstream of the
PLC in peptide-deficient environments as a second pMHC
I quality inspector. TAPBPR is not restricted to the ER but
alsofoundintheGolgicompartment.Initsactionasasecond
quality inspector, TAPBPR likely cooperates with UDP-
glucose:glycoprotein-glucosyltransferase 1 (UGGT1).
UGGT1 is the major folding sensor of glycoproteins in
theERand cis-Golgi. It recognizes incompletefoldingstates
of its client proteins and reglucosylates their Man9GlcNAc2glycan. This crucial decision point prevents misfolded
proteins from leaving the ER by enforcing a re-engagement
with Crt/Cnx and associated chaperones. In the case of
incompletely folded MHC I complexes, reglucosylation by
UGGT1 allows them to (re-)visit the PLC in order to be
loaded with a suitable peptide. Interestingly, TAPBPR has
recently been demonstrated to aid UGGT1 in detecting
peptide-deficient MHC I [24] (Figure 1). Thus, TAPBPR
supports pMHC I maturation in two different ways: first, by
directly acting as a peptide editor, and secondly, by pro-
moting UGGT1-catalyzed reglucosylation and recycling of
the MHC I to Tsn in the peptide-rich environment of the
PLC, if loading in the peptide-scarce environment
TAPBPR operates in is not successful.
In this review, we present the latest insights into the inner
workings of the PLC, the mechanism of peptide editing
by the two MHC I-dedicated chaperones Tsn and
TAPBPR, including the significance of molecular plas-
ticity in this process. These insights have been gained by
single-particle cryogenic electron microscopy (cryo-EM)
and X-ray crystallography of the native PLC and
TAPBPR-MHC I complexes [25��,26��,27��], respec-
tively, but also by carefully designed nuclear magnetic
resonance (NMR) studies, biochemical investigations,
and cell biological experiments.
The PLC as a central hub in MHC I loading andquality controlThe PLC is a supramolecular assembly consisting of
TAP, a heterodimeric type IV ABC peptide transporter
[4,28–30], the disulfide-bridged conjugate of Tsn and
Current Opinion in Immunology 2021, 70:48–56
ERp57, and Crt-bound MHC I [5]. The PLC is embed-
ded in the ER membrane and represents a crucial ele-
ment of the antigen presentation pathway by translocat-
ing short peptides from the cytosol into the ER and by
facilitating peptide loading and proofreading on MHC I.
To hide from the immune system, several DNA viruses
such as Herpesviridae and Poxviridae block effective
immunosurveillance by targeting PLC components.
The immune evasion strategies range from TAP inhibi-
tion to induced degradation of TAP and Tsn [31��,32].For cryo-EM studies, the immune evasin ICP47 of
human herpes simplex virus was utilized as a bait to
isolate native human PLC from a lymphoblastoid cell
line [25��]. Remarkably, the PLC preparation not only
contained HLA-A, HLA-B, and HLA-C, but also the non-
classical, oligomorphic HLA-E, HLA-F, and HLA-G
(and MR1, unpublished results) [25��]. The PLC cryo-
EM reconstructions showed that the fully assembled
complex is composed of two editing modules formed
by Tsn-ERp57 and MHC I-Crt, which are arranged along
a pseudosymmetric axis around the centrally positioned
TAP (Figure 2a). The two TAP subunits (TAP1/2)
possess an extra N-terminal transmembrane domain
called TMD0 that is known to serve as interaction
platform for the transmembrane helix of Tsn [33–35].
The central lumenal framework is built from the two
Tsn molecules, whereas Crt is anchored by its lectin
domain to the N-linked glycan of the MHC I and
interacts with ERp57 via the tip of its elongated, arm-
like, proline-rich (P)-domain (Figure 2b). The long C-
terminal a-helix of Crt contacts the membrane-proximal
IgC1 domain of Tsn. The arrangement of the two edit-
ing modules gives rise to a cavity-like structure above
the lumenal gate of TAP, which has two lateral openings
and might function as a reservoir for translocated pep-
tides (Figure 2a). Notably, subclasses of the cryo-EM
data uncovered asymmetric PLC particles containing
one incomplete editing module, with either MHC I,
Crt, or both being absent, reflecting the transient nature
of the PLC (Figure 2c). Metaphorically speaking, the
PLC might be regarded as a busy cargo loading station
where TAP brings in the supplies, Tsn is the loading
master, and peptide-receptive and peptide-loaded MHC
I complexes come and go. Based on the experimentally
determined reconstruction, the highly dynamic nature of
the PLC has been studied in a solvated lipid bilayer by
all-atom molecular dynamics (MD) simulations [36�](Figure 2c). The simulations on the microsecond time
scale confirm the architectural role of Tsn in forming a
rigid core together with MHC I, while the remaining
constituents are more flexible. Furthermore, the simula-
tions unveil that Crt dampens conformational dynamics
in Tsn and thereby facilitates MHC I recruitment into
the PLC. These results will serve as a base for future
studies on the allosteric crosstalk in this fascinating,
highly dynamic machinery and on the intriguing molec-
ular sociology during viral immune evasion.
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MHC I chaperones in antigen processing Thomas and Tampe 51
Figure 2
ER membrane
cytosol
ER lumen
(a) (b)
Peptide-loading complex (PLC)
2m
MHC hc
Tsn
ERp57
Crt
TAP1
ICP47
peptide
cavity
TMD0 TMD0
(c)
Tsn
MHC I hcERp57
Crt
2m
view from ER lumen
Current Opinion in Immunology
Architecture of the peptide-loading complex (PLC). (a) Single-particle cryo-EM reconstruction of the PLC (PDB codes 6ENY and 5U1D; EM density
maps: EMD-3904-3906) [25��,29]. The fully assembled PLC comprises two editing modules that are arranged around the central ABC peptide
transporter TAP1/2. Each editing module consists of the scaffold chaperone calreticulin (Crt), the oxidoreductase ERp57, the MHC I-specific
chaperone tapasin (Tsn), and the MHC I heterodimer of heavy chain (hc) and b2-microglobulin (b2m). Neither the N-terminal transmembrane
domain 0 (TMD0) of TAP1 and TAP2 nor the transmembrane helices of Tsn and MHC I hc were visible in the cryo-EM map. (b) View from the ER
lumen onto the cryo-EM reconstruction of the PLC. The two Tsn molecules form the central lumenal framework, while Crt is anchored through its
lectin domain to the N-linked glycan of the MHC I hc and interacts with ERp57 via the tip of its arm-like proline-rich (P)-domain. (c) Assembly and
disassembly of the PLC. Peptide-deficient MHC I complexes are escorted by Crt to the asymmetric PLC to assemble into the symmetric PLC
comprising two editing modules. Cytosolic antigenic precursor peptides are translocated by TAP1/2 into a cavity formed by the two editing
modules. After diffusing into the ER lumen through two lateral openings, the peptides are trimmed by ERAP and loaded onto MHC I complexes.
Once the peptide-MHC I complexes have passed Tsn-catalyzed proofreading, they exit the PLC and are licensed to travel to the cell surface via
the Golgi apparatus. The panel figure was prepared using the coordinates of a MD simulation model of the PLC (ModelArchive DOI: https://doi.
org/10.5452/ma-whom2) [36�], and the program Illustrate [71]. The MD model is based on the experimental cryo-EM reconstruction shown in (a)
and (b) [25��] and experimentally determined structures of (homologous) subcomplexes and individual components (homologs), including the
TAPBPR-MHC I complex [26��,72–76]. The lipid bilayer is from the MemProtMD database (PDB code 6RAN) [22��,77].
www.sciencedirect.com Current Opinion in Immunology 2021, 70:48–56
52 Antigen processing
Chaperone function and catalytic mechanismof Tsn and TAPBPRThe two MHC I-dedicated, IFNg-inducible chaperones
Tsn and TAPBPR exhibit 21% sequence identity in their
lumenal regions, which fold into an N-terminal composite
domain of a seven-stranded b-barrel and IgV structure,
and a C-terminal IgC1 domain [37]. While Tsn forms a
disulfide-bonded heterodimer with ERp57 and is inte-
grated into the PLC, the solitary TAPBPR performs its
tasks beyond the PLC and is also found in the Golgicompartment, due to the lack of an ER retention motif
[37]. Both Tsn and TAPBPR specifically recognize and
stabilize ‘frustrated’ MHC I species, that is, those MHC I
complexes which are peptide-deficient or loaded with a
suboptimal, low-affinity peptide. At the same time, Tsn
and TAPBPR enable MHC I complexes to swap peptides
more rapidly and sample out high-affinity ligands
[9–11,14,38,39]. The core principles underlying this chap-
erone and peptide exchange activity of TAPBPR and Tsn
were revealed by two crystal structures of the TAPBPR-
MHC I complex [26��,27��]. The structures show that the
N-terminal domain of TAPBPR clutches the a2-1 helix
region of the MHC I heavy chain, whereas the TAPBPR
C-terminal domain interacts with b2m and the a3 domain
(Figure 3a and b). The concave N-terminal interface
includes a b-hairpin, termed ‘jack hairpin’, which con-
tacts the floor bottom of the MHC I peptide-binding
groove and W60, a conserved tryptophan in b2m. Intrigu-
ingly, the conformation of W60 is sensitive to the loading
status of the groove [40,41], suggesting that the ‘jack
hairpin’ contributes to the ability of TAPBPR to sense
MHC I peptide occupancy. Another structural element of
Figure 3
(a) (b)
Crystal structure of the complex between the MHC I-specific peptide proofr
code 5OPI). (a) and (b) Overview of the TAPBPR-MHC I complex, highlighti
TAPBPR is depicted in cartoon representation, whereas MHC I hc and b2m
contacts with its N-terminal composite b-barrel-IgV domain and its C-termin
hc, but also b2m. (c) View onto the chaperoned peptide-receptive MHC I bi
region.
Current Opinion in Immunology 2021, 70:48–56
TAPBPR, the so-called ‘scoop loop’, dips into the
F-pocket region of the MHC I [26��], where the C
terminus of bound peptides is anchored and whose role
in governing pMHC I stability has been established
[42,43] (Figure 3c). A highly conserved tyrosine (Y84)
of MHC I near the F pocket that coordinates the C
terminus of the peptide in the ligand-bound state is also
swung out of its normal position and coordinated by the
side chain of E105 in TAPBPR. The Y84-E105 pair could
be regarded as a switch promoting peptide exchange and
selection. Indeed, the glutamate is found in Tsn as well
and has previously been shown to contribute to catalysis.
The ‘scoop loop’ has only been modeled in one of the two
TAPBPR-MHC I complexes, but due to its position in a
key region of the binding groove, the ‘scoop loop’ has
been proposed to be involved in the proofreading activity
[26��]. This notion has been corroborated by several
studies using independent approaches [44��,45��,46��],with one of them highlighting the importance of a specific
leucine residue in the loop for peptide exchange and
showing how the physico-chemical properties of the F
pocket influence loop-mediated TAPBPR activity [44��].A second study demonstrated that the ‘scoop loop’ is
critical to chaperoning empty MHC I and functions as a
selectivity filter during peptide editing [45��]. Further-
more, the ‘scoop loop’ appears to function as a selectivity
filter in Tsn-catalyzed proofreading as well [46��]. The
recent all-atom MD simulations of the PLC signify that
the N-linked glycan of the MHC I affects the conforma-
tional dynamics of the Tsn ‘scoop loop’ and steers it
toward the peptide-binding groove [36�]. However, the
exact conformation of the shorter Tsn ‘scoop loop’ and its
(c)
Current Opinion in Immunology
eader and chaperone TAPBPR and peptide-deficient MHC I (PDB
ng the tight interaction between chaperone and the MHC I complex.
are shown with their solvent-excluded (‘Connolly’) surface. TAPBPR
al IgC1 domain not only the a2-1 region and a3 domain of the MHC I
nding groove, with the TAPBPR scoop loop positioned in the F-pocket
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MHC I chaperones in antigen processing Thomas and Tampe 53
interaction with the MHC I in the context of the Tsn-
ERp57-MHC I complex remains to be determined exper-
imentally. A comparison of the TAPBPR-complexed
MHC I structures with structures of free, peptide-bound
MHC I discloses several conformational changes in the
complexed MHC I: a widening of the binding groove due
to a shift of the a2 helices, a downward movement of the
groove floor, as well as a positional change of b2m relative
to the heavy chain. NMR experiments support these
observations and confirm the concept that conformational
plasticity is a key property of proteins involved in MHC I
peptide loading and proofreading [47��,48–54,55��].Moreover, the NMR investigations indicate that different
sites of the peptide-binding groove communicate alloste-
rically, with strong coordination of an optimal peptide in
the N-terminal pocket being conveyed to the C-terminal
region, leading to TAPBPR dissociation. In essence, the
experimental evidence on catalyzed peptide loading and
editing collected so far suggests that TAPBPR and Tsn
are able to sense the MHC I loading status by sampling
structural elements that mediate high-affinity ligand
interaction. Editor binding stabilizes an ensemble of
high-energy MHC I conformations characterized by an
open binding groove that is associated with accelerated
peptide exchange. The presence of TAPBPR lowers the
affinity of peptides for the MHC I groove 100-fold [47��],and only high-affinity peptides are able to induce disso-
ciation of the editor by competing over critical peptide-
coordinating regions. As a result of the catalyzed editing
process, the MHC I-bound epitope repertoire is opti-
mized such that the pMHC I complexes at the cell surface
are kinetically stable enough to be scanned by the com-
binatorial repertoire of patrolling T and NK cells.
Editor specificities and intrinsic selectorcapabilities of different allomorphsBoth Tsn and TAPBPR recognize empty or suboptimally
loaded pMHC I complexes, and, while some differences
in allomorph and peptide specificities exist [9], the two
editors share overall a common substrate preference and
binding hierarchy [56��]. In general, in its function as
chaperone, TAPBPR seems to exhibit a broader client
specificity than in its role as quality inspector of properly
folded pMHC I [55��]. In order to be recognized by
TAPBPR, pMHC I complexes have to be in an excited
state, and the corresponding conformation is adopted by
only 3–6% of the whole pMHC I population [55��].TAPBPR prefers HLA-A allomorphs, in particular mem-
bers of the HLA-A2 and HLA-A24 superfamilies, over
HLA-B and HLA-C representatives, with HLA-A*68:02
being the strongest binder reported so far [56��]. How-
ever, there are exceptions to the preference for HLA-A,
including A*01:01, A*11:01, A*36:01, A*26:01, and
A*68:01, for which no significant TAPBPR binding was
observed [10,56��]. As far as the general susceptibility to
proofreading is concerned, positions 114, 116, 147, and
156 in human MHC I allotypes have been demonstrated
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to be key in governing chaperone dependence as they
determine the stability of empty MHC I [49,57,58�]. An
extreme case are the two allotypes B*44:02 and B*44:05:
they differ only at position 116 on the floor of the binding
groove, but while B*44:02 is Tsn-dependent, B*44:05 has
the intrinsic ability to select peptides independently of
Tsn [38,49,59��]. Some evidence suggests that the ability
of allomorphs to intrinsically select peptides is deter-
mined by their plasticity [49], while other data indicate
that the difference in Tsn dependence of the two B*44
allotypes is due to a more closed, stable conformation of
the F pocket region in the B*44:05 binding groove in the
peptide-deficient state [53,60]. A similar correlation
between stability of the F pocket region and Tsn depen-
dence has been described for B*27:05 and B*27:09 [61],
where B*27:05 is strongly associated with the disease
ankylosing spondylitis. These examples underline the
importance of protein dynamics in intrinsic and assisted
peptide selection on MHC I.
Intriguingly, the substrates of Tsn and TAPBPR are not
restricted to classical MHC I: Surface expression of HLA-
E is TAP- and Tsn-dependent [62,63], and HLA-E,
HLA-F, and HLA-G have been found to be associated
with the PLC [25��], with potential implications for the
immunosurveillance of viruses and vaccine development
[64]. Most remarkably, the two editors also stabilize ER-
resident, unliganded MR1 (MHC class I-related protein 1),
a non-classical MHC I that presents exogenous microbial
vitamin B metabolites as antigens (VitBAg) to innate-like
mucosal-associated invariant T (MAIT) cells [65��].Ligand association is unusual in the case of MR1, as VitBAg
forms a covalent Schiff base with a lysine residue in the
binding groove of MR1 [66,67]. While ligand-receptive
MR1in theER stronglyassociateswith Tsn, the interaction
with TAPBPR is weaker, but both chaperones appear to
cooperate in preventing MR1 degradation and increasing
surface expression [65��]. Notably, the role of Tsn and
TAPBPR in VitBAg presentation is not to facilitate loading
but to increase the half-life of empty MR1 in the ER, and
suitable ligands for MR1 are likely selected without the
help of an editor just by their ability to form the Schiff base
[65��].
ConclusionThe sophisticated cellular machinery of antigen proces-
sing and presentation provides a representative, MHC I-
displayed peptidome that allows for highly specific T cell-
mediated responses which are vitally important for adap-
tive immunity. During their life cycle, MHC I molecules
and complexes are diligently looked after by folding
helpers and conformational sensors, loading assistants,
and quality inspectors. At many stages, defined variants
of the N-linked glycan enable the MHC I clients to be
recognized by binding partners and to be dispatched to
proper cellular destination. The last few years have seen
tremendous progress in our understanding of mechanistic
Current Opinion in Immunology 2021, 70:48–56
54 Antigen processing
and physiological principles governing peptide loading,
editing, and quality control on MHC I. It has become
apparent that Tsn and TAPBPR work in tandem in a
complementary fashion and that plasticity of the involved
protagonists is of utmost importance. The crystal struc-
tures of the TAPBPR-MHC I complex have unearthed
key elements of catalyzed peptide exchange, including
the jack hairpin, the Y84-E105 switch, and the scoop loop.
Yet, despite their individual importance, these elements
and other regions in the exceptionally large chaperone-
client interaction network have to interplay and crosstalk
allosterically in a concerted and integrative manner to
bring about the observed catalytic effect. In addition to
Tsn and TAPBPR, a fine-meshed net of ER/Golgi cha-
perones is concerned with pMHC I maturation, including
the major glycoprotein folding sensor UGGT1. The
advanced understanding of pMHC I maturation has
already paid dividends: TAPBPR can be utilized to load
immunogenic peptides onto cells and to generate pMHC
I tetramer libraries to identify antigen-specific T cells in
the development of new diagnostics and cancer immu-
notherapies [68�,69�,70]. We expect that additional fields
that aim to tailor antigen presentation for therapeutic
purposes will be able to leverage the deeper insights.
Declaration of interestNone.
AcknowledgementsWe thank Andrea Pott, Inga Nold, and all members of the Institute forBiochemistry for discussion and many helpful comments. This research wassupported by the German Research Foundation (CRC 807/P16 to R.T. andthe Reinhart Koselleck Project TA 157/12-1 to R.T.) and by an ERCAdvanced Grant (789121 to R.T.) of the European Research Council.
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Hofmann S, Januliene D, Mehdipour AR, Thomas C, Stefan E,Bruchert S, Kuhn BT, Geertsma ER, Hummer G, Tampe R et al.:Conformation space of a heterodimeric ABC exporter underturnover conditions. Nature 2019, 571:580-583
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Jiang J, Natarajan K, Boyd LF, Morozov GI, Mage MG,Margulies DH: Crystal structure of a TAPBPR-MHC I complexreveals the mechanism of peptide editing in antigenpresentation. Science 2017, 358:1064-1068
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These papers deliver insights into the role of a structural element in thechaperone and editing activities of TAPBPR and Tsn.
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McShan AC, Natarajan K, Kumirov VK, Flores-Solis D, Jiang J,Badstubner M, Toor JS, Bagshaw CR, Kovrigin EL, Margulies DHet al.: Peptide exchange on MHC-I by TAPBPR is driven by anegative allostery release cycle. Nat Chem Biol 2018, 14:811-820
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Ilca FT, Drexhage LZ, Brewin G, Peacock S, Boyle LH: Distinctpolymorphisms in HLA class I molecules govern theirsusceptibility to peptide editing by TAPBPR. Cell Rep 2019,29:1621-1632.e3
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