The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

Review Articles

Advances in Immunology plasmic tail (Fig. 2). There are some 20 class I genes
in the HLA region; three of these, HLA-A, B, and
C, the so-called classic, or class Ia genes, are the main
IAN MACKAY, M.D., AND FRED S. ROSEN, M.D., actors in the immunologic theater.
Editors The class II genes code for the a and b polypeptide
chains of the class II molecules (Fig. 2). The desig-
nation of their loci on chromosome 6 consists of three
T HE HLA S YSTEM letters: the first (D) indicates the class, the second
(M, O, P, Q, or R) the family, and the third (A or B)
First of Two Parts the chain (a or b, respectively). HLA-DRB, for ex-
ample, stands for class II genes of the R family cod-
JAN KLEIN, PH.D., AND AKIE SATO, PH.D. ing for the b chains. The individual genes of the HLA
system are differentiated by Arabic numbers, and the
notation for the numerous allelic variants of these
genes is a number preceded by an asterisk. For ex-

A
MAN dies because his body has rejected a
heart transplant; a woman is crippled by rheu- ample, HLA-DRB1*0401 stands for allelic variant
matoid arthritis; a child goes into a coma that 0401 of gene 1, which encodes the b chain of a class
is brought on by cerebral malaria; another child dies II molecule belonging to the R family. Each of the
of an infection because of an immunodeficiency; an class II a and b chains has four domains: the pep-
elderly man has advanced hepatic cirrhosis caused by tide-binding domain (a1 or b1), the immunoglobu-
iron overload. These five clinical situations are as di- lin-like domain (a 2 or b 2), the transmembrane re-
verse as can be, yet all have one thing in common: the gion, and the cytoplasmic tail (Fig. 2).
cause of all of them involves the human leukocyte an- Class I genes are expressed by most somatic cells,
tigen (HLA) system, the human version of the major although the level of expression varies depending on
histocompatibility complex (MHC). Malfunction of the tissue.1 By contrast, class II genes are normally ex-
the HLA system, which is at the root of these and pressed by a subgroup of immune cells that includes
many other clinical disorders, has such wide-ranging B cells, activated T cells, macrophages, dendritic cells,
effects not only because of the system’s role in the and thymic epithelial cells.1 In the presence of inter-
adaptive immune response, but also because of its feron-g, however, other types of cells can express
genetic complexity. class II HLA molecules. The function of both class
The HLA complex on chromosome 6 contains over I and class II molecules is the presentation of short,
200 genes, more than 40 of which encode leukocyte pathogen-derived peptides to T cells, a process that
antigens (Fig. 1).1-3 The rest are an assortment of genes initiates the adaptive immune response. To under-
that are not evolutionarily related to the HLA genes stand this function, it is necessary to place it in the
themselves, although some are involved with them context of the cell’s physiology, in particular the proc-
functionally.4 Many genes within this complex have ess of waste disposal.
nothing to do with immunity. The HLA genes that ANTIGEN PROCESSING
are involved in the immune response fall into two AND PRESENTATION
classes, I and II, which are structurally and function-
ally different (Fig. 2). The class I genes code for the Cells are equipped with an enviably clean and ef-
a polypeptide chain of the class I molecule; the ficient system of waste disposal and recycling. A spe-
b chain of the class I molecule is encoded by a gene cial molecule, ubiquitin, marks worn-out proteins for
on chromosome 15, the beta2-microglobulin gene. dumping (Fig. 3A). These proteins unfold with the
The a chain has five domains: two peptide-binding help of other specialized molecules, the chaperones,
domains (a1 and a2), one immunoglobulin-like do- and the polypeptide chains are then fed into barrel-
main (a3), the transmembrane region, and the cyto- shaped structures, the proteasomes, which chop them
up into short fragments.5 The peptides emerging from
the proteasome are either degraded into amino acids
in the cytosol or transferred into the endoplasmic
From the Max-Planck-Institut für Biologie, Abteilung Immungenetik, reticulum.
Tübingen, Germany. Address reprint requests to Dr. Klein at the Max-Planck- Extracellular proteins take a different route to deg-
Institut für Biologie, Abteilung Immungenetik, Corrensstr. 42, D-72076
Tübingen, Germany, or at jan.klein@tuebingen.mpg.de. radation (Fig. 3B). They are herded into small bags
©2000, Massachusetts Medical Society. that invaginate from the plasma membrane into the

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 A DVA N C E S I N I M M U N O L O GY

Chromosome 6 q Centromere p

6p21.31
Telomere Telomere

Regions

Class II Class III Class I

PSMB9 (LMP2)

PSMB8 (LMP1)
HLA class II%
region loci
TAPBP

DQA1
DQB1

DRB1
DRB2

DRB3
DPB2
DPB1
DPA1

TAP1

TAP2
DMA
DMB
DOA

DOB

DRA
HLA class III%
P450, C21B

region loci
HSPA1A
HSPA1B

HSPA1L

TNF-a-
C4A
C4B

LTB

LTA
BF
C2

HLA class I %
region loci

HLA-G
HLA-A
HLA-C
HLA-B

HLA-E

HLA-F
MICA
MICB

HFE
Figure 1. Location and Organization of the HLA Complex on Chromosome 6.
The complex is conventionally divided into three regions: I, II, and III. Each region contains numerous loci (genes), only some of
which are shown. Of the class I and II genes, only the expressed genes are depicted. Class III genes are not related to class I and
class II genes structurally or functionally. BF denotes complement factor B; C2 complement component 2; C21B cytochrome P-450,
subfamily XXI; C4A and C4B complement components 4A and 4B, respectively; HFE hemochromatosis; HSP heat-shock protein;
LMP large multifunctional protease; LTA and LTB lymphotoxins A and B, respectively; MICA and MICB major-histocompatibility-
complex class I chain genes A and B, respectively; P450 cytochrome P-450; PSMB8 and 9 proteasome b 8 and 9, respectively; TAP1
and TAP2 transporter associated with antigen processing 1 and 2, respectively; TAPBP TAP-binding protein (tapasin); TNF-a tumor
necrosis factor a; and HSPA1A, HSPA1B, and HSPA1L heat-shock protein 1A A-type, heat-shock protein 1A B-type, and heat-shock
protein 1A–like, respectively.

cytoplasm. The bags are then pinched off as endocyt- originating from the pathogen are also routed into
ic vesicles, and they fuse with primary lysosomes, the processing pathways. With the exception of jawed
which are loaded with an assortment of proteolytic vertebrates, no organisms appear to make a distinction
enzymes, to form endosomes.5 Within the endo- between peptides derived from their own (self ) pro-
somes, the ingested proteins are degraded, first to teins and those derived from foreign (nonself ) pro-
peptides and then, in some vesicles, into amino acids teins. Jawed vertebrates, by contrast, use the peptides
for reuse. derived from foreign (usually microbial) proteins to
This mode of protein processing must have evolved mark infected cells for destruction.
at an early stage in the history of living forms. Later, In an uninfected cell, “housekeeping” proteasomes
the jawed vertebrates found a new use for it by en- continuously churn out self peptides, some of which
listing it in the defense of the body against patho- are picked up by molecules called “transporters asso-
gens. Normally, the proteins that undergo recycling ciated with antigen processing,” or TAPs, encoded by
are the organism’s own, but in infected cells, proteins the TAP1 and TAP2 genes.5 The TAP1 and TAP2

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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

way to the luminal surface of the endoplasmic retic-

Class I Class II ulum. There, the emerging chains are attended by a
Peptide-binding? suite of molecular chaperones — calnexin, calreticu-
groove lin, endoplasmic reticulum p57, TAP-binding pro-
tein (also referred to as tapasin), and perhaps others
a2 a1 — which ensure that the polypeptides do not fold
a1 b1 prematurely, that they are properly glycosylated, that
the a chain meets beta2-microglobulin at the appro-
priate time, and that when this moment comes, the
union proceeds without a hitch. A class I molecule
a3 b2m a2 b2 is then pinioned by the TAP-binding protein to the
TAP molecule for loading. When a suitable peptide
emerges from the TAP channel, the peptide-binding
groove (Fig. 2) of the waiting class I molecule snags
TM TM TM it. The loaded molecule then undocks from the com-
plex of TAP-binding protein and TAP and sets off
Plasma? on a journey to the surface of the cell. There, the
membrane class I molecule remains anchored in the plasma mem-
Cytoplasmic? Cytoplasmic? brane by the transmembrane region of the a chain.
tail tail In this position, it displays the bulk of the a chain
(the a1, a 2, and a3 domains shown in Fig. 2), the
peptide, and the associated beta2-microglobulin to
Figure 2. Structure of HLA Class I and Class II Molecules. other cells.
Beta2-microglobulin (b2m) is the light chain of the class I mole- In the meantime, the class II molecules are also
cule. The a chain of the class I molecule has two peptide-bind- preparing to receive peptides generated by the en-
ing domains (a1 and a2), an immunoglobulin-like domain (a3),
the transmembrane region (TM), and the cytoplasmic tail. Each docytic protein-processing pathway (Fig. 3B).5 Like
of the class II a and b chains has four domains: the peptide- the two chains of class I molecules, those of class II
binding domain (a1 or b1), the immunoglobulin-like domain molecules are manufactured separately on the cyto-
(a2 or b2), the transmembrane region, and the cytoplasmic tail. solic surface of the endoplasmic reticulum and then
brought together, folded, and assembled on the lu-
minal surface of the structure with the assistance of
proteins interact to form a channel for transporting chaperones. Unlike class I molecules, however, class
peptides across the membrane of the endoplasmic II molecules are not loaded with peptides in the en-
reticulum. Peptides released by proteasomes bind to doplasmic reticulum. Instead, they associate with a
the cytosolic surface of the TAP molecule and are fer- protein produced in the endoplasmic reticulum, the
ried through this channel. On the luminal surface of invariant chain, part of which acts as a stopper for
the endoplasmic reticulum, queuing up like trucks the peptide-binding groove and thereby precludes
waiting to be loaded with cargo, are the class I mol- premature loading of peptides. Enclosed in membra-
ecules (Fig. 3A). The two polypeptide chains of the nous vesicles, the complexes of class II molecules and
class I molecules, the a chain and the beta2-micro- invariant chains journey to the region of the cytoplasm
globulin, are manufactured separately on ribosomes in which they intersect with endosomes with their car-
attached to the cytosolic surface of the endoplasmic go of exogenous proteins.5 The transporting vesicles
reticulum, but as they come off the assembly line, and the endosomes fuse to form the MHC class II
they thread through special channels to make their compartment, in which proteases degrade the exog-

Figure 3 (facing page). Antigen Processing.

Panel A shows the principal pathways of generating peptides for loading onto HLA class I molecules. Worn-out or defective proteins
in the cytosol are degraded into peptides in proteasomes. Selected peptides are then transported into the endoplasmic reticulum,
where they are loaded onto newly synthesized class I molecules. The HLA–peptide complexes are exported by way of the Golgi
apparatus to the surface of the cell. In tissues infected with a virus, viral particles are taken up by cells and uncoated. The viral DNA
or RNA enters the nucleus and replicates within it. The viral messenger RNA (mRNA) then enters the cytosol and is transcribed
into proteins. Some of the proteins are subsequently degraded in proteasomes, and the peptides are delivered into the endoplasmic
reticulum, where they are loaded onto class I molecules for export to the surface of the cell. Panel B shows the processing of ex-
tracellular proteins. Self or foreign proteins are taken up by endocytosis (or phagocytosis) and sequestered into endosomes. Class
II molecules synthesized in the endoplasmic reticulum are delivered by way of the Golgi apparatus into primary lysosomes, which
fuse with the early endosomes to form the major-histocompatibility-complex (MHC) class II compartment. Enzymes brought into
this compartment by the lysosomes degrade the engulfed proteins into peptides. HLA-DM molecules synthesized in the endoplasmic
reticulum and delivered into the MHC class II compartment by transport vesicles help load the peptides onto the class II molecules.
The HLA–peptide complexes are then exported to the surface of the cell.

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 A DVA N C E S I N I M M U N O L O GY

A
Virus

Receptor

Phagocytosis
Cytoplasm

Nucleus
Exocytosis

Viral RNA or DNA

Endoplasmic?
reticulum
Replication
HLA–peptide?
complex
Viral mRNA?
? Defective?
Golgi apparatus
protein

Proteasome
? HLA class I?
Viral mRNA? Protein
? molecule ? Peptide
Proteasome

B Extracellular self or foreign protein

Early?
Cytoplasm endosome MHC class II?
Endocytosis Primary? compartment
lysosome
Degradation?
of protein
Nucleus HLA class II?
molecule HLA-DM

Exocytosis

HLA–peptide?
complex
%
HLA-DM
Endoplasmic?
reticulum HLA-DM

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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

enous proteins and the bulk of the invariant chain tor 9 and the CD4–CD8 coreceptors.10 The ligands
(the class II molecules being remarkably resistant to for both are the HLA–peptide complexes, but the
the action of these enzymes). This process leaves be- T-cell receptor engages the peptide and the peptide-
hind the piece of the invariant chain that functions binding part of the HLA molecule, whereas the CD4–
as a stopper in the peptide-binding groove. Ultimate- CD8 coreceptors interact with parts outside the pep-
ly, however, the stopper is also dislodged by class II tide-binding groove.
molecules specialized in this task (HLA-DM), and a Maturing thymocytes express both CD4 and CD8
peptide derived from an exogenous protein slips into molecules (i.e., they are CD4+CD8+), but the en-
the groove. The peptide-laden class II molecules are gagement of these cells with HLA molecules causes
then exported to the surface of the cell. the down-regulation of one and the up-regulation of
Protein processing and loading of peptides onto the other, resulting in mature T cells of either the
class I molecules are taking place all the time in most CD4+CD8¡ type or the CD4¡CD8+ type.11 Which
cells. There is always plenty of material to feed the of the two CD molecules the cell ultimately express-
processing machinery, because worn-out, damaged, es is determined by the T-cell receptor. Some T-cell
and misfolded proteins are continuously being de- receptors interact preferentially with class I and oth-
graded and replaced by new ones. In addition to proc- ers with class II molecules, depending on the speci-
essing by proteasomes, some proteins are also degrad- ficity of their variable (V) domains, in particular the
ed into peptides by soluble enzymes in the cytosol.6 germ-line–encoded complementarity-determining re-
By contrast, the processing of exogenous proteins gions 1 and 2 (CDR1 and CDR2, respectively) borne
and the loading of peptides onto class II molecules are by the a chain.
normally restricted to B cells, macrophages, and den- The T-cell–receptor molecule consists of two poly-
dritic cells, which are very efficient in taking up ma- peptide chains, a and b, each of which has a vari-
terial by endocytosis or phagocytosis. Although most able and a constant domain. In the V domain, the
class I and class II molecules form complexes with highest degree of amino acid variability is concen-
peptides derived from endogenous and exogenous trated in three segments: CDR1, CDR2, and CDR3.
proteins, respectively, this demarcation is by no means The names of these regions refer to the fact that in
absolute. Class I molecules containing peptides de- the three-dimensional depiction of the molecule, they
rived from exogenous (e.g., bacterial) proteins and form loops that project like fingers from a grasping
class II molecules laden with peptides generated from hand to grip the HLA–peptide complex according
endogenously synthesized (e.g., viral) proteins exist, to the principle of spatial complementarity. The vari-
but how these complexes arise is not entirely clear.5 ability of CDR1 and CDR2 is inherited through the
The consequence of protein processing is that the germ line, whereas that of CDR3 is largely generat-
surfaces of cells become adorned with peptide-laden ed somatically during the maturation of each T cell.
HLA molecules, amounting on a per cell basis to The ability of the T-cell receptor to discriminate be-
roughly 100,000 to 300,000 class I or class II prod- tween class I and II molecules is so refined that the
ucts of each of the highly expressed HLA loci.7 Since replacement of a single amino acid at a critical posi-
each HLA molecule has one peptide bound to it, tion in the receptor’s Va region can change the spec-
each uninfected cell displays hundreds of thousands ificity of the T-cell receptor from one HLA class to the
of self peptides on its surface. Some of these peptides other.12 A thymocyte whose T-cell receptor engages
are present in the thousands, whereas others are rep- a complex of an HLA class I and a peptide generally
resented by a few copies; most peptide species have also engages its CD8 coreceptors and down-regulates
100 or so copies on the surface of each cell. Each cell the expression of the unengaged CD4 molecules. The
thus displays a heterogeneous collection of peptides, reverse happens to a thymocyte whose T-cell recep-
and the surface of a cell resembles rows of well- tor has engaged a complex of an HLA class II mol-
stocked stalls at a bazaar, with bargain hunters scruti- ecule and a peptide: it becomes a CD4+ cell. Re-
nizing the wares. But if, in this metaphor, the vendors striction of the maturing T cells to the expression of
are the HLA molecules and the peptides the goods, either CD4 or CD8 molecules is accompanied by
who are the potential buyers? They are a group of lym- the specification of a developmental program and
phocytes reared in the thymus and then turned loose thus, ultimately, determination of the function of the
to roam the body — the T cells. cell. Generally, CD4+ T lymphocytes become help-
er T cells that elicit responses from B cells and mac-
HLA AND SELECTION IN THE THYMUS rophages, whereas CD8+ T lymphocytes become
The lymphocyte progenitors entering the thymus cytotoxic T cells capable of eliminating target cells
are programmed to die unless they receive signals in- identified by the interaction of the T-cell receptor
structing them to differentiate further.8 These signals and the HLA–peptide complex.2
emanate from an interaction that involves the epithe- As progenitor cells enter the thymus and proceed
lial component of the thymus and several species of toward the center, dividing and differentiating along
molecules, two of which are critical: the T-cell recep- the way,11 they express their T-cell receptor genes in

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 A DVA N C E S I N I M M U N O L O GY

such a way that each clone produces a receptor spe- ceptors displayed by a single T cell become engaged
cific for a different ligand. As they enter the thymic by a ligand, the T cell is activated to differentiate ei-
cortex, thymocytes are given the opportunity to match ther into a CD8+ cytotoxic killer T cell (if the en-
their newly formed receptors with the abundant gaging HLA molecule is of the class I type) or into
HLA–peptide complexes on cortical epithelial cells. a CD4+ helper T cell (if the engagement involves a
Most of these thymocytes do not find ligands that class II molecule).14 The activities of the stimulated
fit the combining sites of their receptors, and since helper T cell include the production of interferon-g,
this means that they receive no signal to justify their along with other cytokines.
further existence, they die “by neglect.” Only a mi- Interferon-g binds to the regulatory regions of se-
nority of thymocytes capable of weakly (i.e., with a lected genes, including the class II genes and loci that
low affinity) engaging their receptors with HLA–pep- control specialized subunits of proteasomes. The bind-
tide complexes receive a signal that blocks the path- ing enhances the expression of these genes, increas-
way to apoptosis (i.e., they undergo positive selec- ing the number of class II molecules on antigen-pre-
tion).11 The interaction is not strong enough to hold senting cells and altering the composition of the
the thymocyte to a cortical epithelial cell, and after subunits of proteasomes.5,15 These modified “immu-
they have disengaged, the thymocyte moves deeper noproteasomes” are more effective than housekeep-
into the thymus. ing proteasomes at generating peptides for loading
At the corticomedullary junction and then in the onto the class I molecules. Both processes enhance
medulla, thymocytes run into hordes of macrophag- the ongoing immune response.
es and dendritic cells (which together are the anti-
gen-presenting cells) that display large quantities of INTERACTIONS BETWEEN T-CELL
HLA–peptide ligands. The thymocytes are given a RECEPTORS AND COMPLEXES OF HLA
second chance to find a match for their receptors, MOLECULES AND PEPTIDES
but the setting in which this new trial takes place has The peptide-binding groove of an HLA molecule
changed. These medullary antigen-presenting cells consists of two parts, a floor and two walls (Fig. 4).
are not just passive displayers of HLA–peptide com- In the floor, the a chain of the class I molecule or
plexes; they also express molecules that provide co- the a and b chains of the class II molecule meander
stimulatory signals to the maturing thymocytes. to form a rather flat structure, the b-pleated sheet.
Medullary antigen-presenting cells not only ex- In each of the two walls, the chain is coiled into an
press costimulatory molecules that differ from those a helix. In the class I peptide-binding groove, the
of the cortical epithelial cells but also express differ- ends of the a helixes of the a1 and a2 domains con-
ent proteases (cathepsins) in their lysosomes by which verge to close the groove,16 whereas in the class II
they process the invariant chain and other proteins.13 molecules, the groove is open-ended.17 Consequent-
As a consequence of these and other differences, a ly, the closed class I groove accommodates shorter
stronger interaction (i.e., one with a higher affinity)
between T-cell receptors and HLA–peptide ligands
becomes possible, and when it takes place, it generates
a signal instructing the thymocytes to undergo apop-
tosis. In this manner, the population of medullary thy-
mocytes is purged of most self-reactive cells that might
otherwise initiate an autoimmune response (i.e., it un-
dergoes negative selection).11
Cells that survive both positive and negative se-
lection leave the thymus and enter the periphery as a1 Helix
naive T cells. Of all the progenitor cells that enter the
thymus and proliferate in it, less than 1 percent ma- b-Pleated sheet?
ture into T cells. In the periphery, naive T cells are ?
probably kept alive by low-affinity interactions with a2 Helix
complexes of HLA molecules and self peptides. Dur-
ing an infection, T cells that bind to complexes of
HLA molecules and foreign peptides with high affinity
are stimulated to initiate an immune response. Thus,
high-affinity interactions between T-cell receptors of
immature cells in the thymus lead to apoptosis, where-
as in the periphery they result in cellular proliferation. Figure 4. Ribbon Model of the Tertiary Structure of an HLA
The mechanisms responsible for this difference in be- Class I Peptide-Binding Module.
havior remain unidentified. The model is shown from the top. The b-pleated sheets are
Once a few hundred of the more than 10,000 re- composed of the a chain.

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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

A Peptides Peptide%
A %
%
P1 P2 P3 P4 P5 P6 P7 P8 P9 a2 Helix NH3+ a1 Helix
W L S L L V P F V
HLA-A*0201 L L F G V P V Y V CDR1 a Chain of?
I L K E P V H G Y T-cell receptor
HLA%
R L R P G G K K K CDR3
molecule CDR2 CDR2
HLA-A3 I L R G S V A H K CDR3
R L R A E A G V K b Chain of?
K T G G P I Y K R CDR1 T-cell receptor
HLA-A*6801 E V A P P E Y H R
A V A A V A A R R
G P G P Q P G P L COO–?
HLA-B7 I P Q C R L T P L
Peptide-binding ?
P P P I F I R R L
groove
R R V K E V V K K B
T cell
HLA-B27 G R I D K P I L K
R R I K E I V K K Plasma membrane

B P4 P5 a2 b2
P8 T-cell?
Peptide P1 COO–? receptor
NH3+ P7
Pockets? P6 P9
P3 a1 b1
of an HLA? P2

CDR3

CDR3
CDR2

CDR2
molecule

A B D C E F Peptide?
? a1 a1
Peptide-binding ?
Figure 5. Interactions between HLA Molecules and Peptides. groove
Panel A shows examples of peptide motifs. The listed nonam-
ers, as well as many others,7 have been found in complexes
with the indicated HLA class I molecules. The anchor residues a3 b2m HLA
are highlighted in yellow. In Panel B, a longitudinal section
through the peptide-binding groove of an HLA class I molecule,
the side chains of amino acid residues composing the bound
peptide (P1 through P9) are oriented either down into the pock-
ets of the HLA molecule or up. The following amino acids are Plasma membrane
shown: alanine (A), cysteine (C), aspartic acid (D), glutamic
acid (E), phenylalanine (F), glycine (G), histidine (H), isoleucine
(I), lysine (K), leucine (L), proline (P), glutamine (Q), arginine Antigen-presenting cell
(R), serine (S), threonine (T), valine (V), tryptophan (W), and ty-
rosine (Y).
Figure 6. Interactions between a T-Cell Receptor and the HLA–
Peptide Complex.
Panel A shows the diagonal orientation of the T-cell receptor on
peptides (7 to 15 residues long) than the open class the surface of the HLA–peptide complex. Panel B shows the
II groove; the longer ones either buckle up in the bridge between a T cell and the antigen-presenting cell created
middle or, much less frequently, hang over the wall at by the interaction between the T-cell receptor and the HLA–
peptide complex. Complementarity-determining region 1 of the
one end. The orientation of the bound, stretched-out a and b chains of the T-cell receptor is not visible in this depic-
peptides is fixed: their N terminals are always posi- tion because one is positioned behind and the other in front of
tioned at the same end of the groove as defined by the part shown. Beta2-microglobulin (b2m) is the light chain of
the orientation of the HLA polypeptide chains, with the class I molecule. The three complementarity-determining
the C terminals at the opposite end. regions (CDR1, CDR2, and CDR3) are shown.
The side chains of the amino acid residues in the
middle of the peptide protrude out of the groove,
whereas those of most of the remaining residues point
into the groove and are housed in specialized small

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 A DVA N C E S I N I M M U N O L O GY

cavities, or pockets, in the groove’s floor.16,18 Typically, REFERENCES

an HLA class I molecule has six pockets (A through 1. Klein J. Natural history of the major histocompatibility complex. New
F) distributed along the length of the groove (Fig. 5). York: John Wiley, 1986.
2. Klein J, Hořejší V. Immunology. 2nd ed. Oxford, England: Blackwell
Two or three of the pockets (in HLA-A, B, or C mol- Scientific, 1998.
ecules, usually pockets B and F) are particularly in- 3. Forbes SA, Trowsdale J. The MHC quarterly report. Immunogenetics
fluential in determining which peptide a molecule 1999;50:152-9.
4. Klein J, Sato A. Birth of the major histocompatibility complex. Scand
binds, because the side chains that fit into them J Immunol 1998;47:199-209.
serve as the peptide’s anchors.7 The remaining pock- 5. Parham P, ed. Pathways of antigen processing and presentation. Immu-
nological reviews. Vol. 172. Copenhagen, Denmark: Munksgaard, 1999.
ets are less important in determining the binding spec- 6. Glas R, Bogyo M, McMaster JS, Gaczynska M, Ploegh HL. A proteo-
ificity. The residues lining the pockets are encoded in lytic system that compensates for loss of proteasome function. Nature
genetic segments defined by the individual alleles of 1998;392:618-22.
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