Immunobiology of the human MHC class I chain

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Revisión
Inmunología
Vol. 25 / Núm 1/ Enero-Marzo 2006: 25-38
Immunobiology of the human MHC class I chain-related
gene A (MICA): from transplantation immunology
to tumor immune escape
Norberto W. Zwirner, Mercedes B. Fuertes, María V. Girart, Carolina I. Domaica, Lucas E. Rossi
Laboratorio de Inmunogenética, Hospital de Clínicas «José de San Martín», and Departamento de Microbiología, Facultad de Medicina,
Universidad de Buenos Aires, Buenos Aires, Argentina.
.
INMUNOBIOLOGÍA DE MICA (HUMAN MHC CLASS I CHAIN-RELATED GENE A):
DESDE LA INMUNOLOGÍA DE TRANSPLANTES HASTA EL ESCAPE TUMORAL
Recibido: 28 Febrero 2006
Aceptado: 20 de Marzo 2006
RESUMEN
El gen MICA (MHC class I chain-related gene A) codifica para
una glicoproteína de superficie distantemente relacionada con las
moléculas de clase I del CMH. MICA es polimórfica, no se asocia
a β2-microglobulina y se expresa en tumores, epitelio gastrointestinal, células endoteliales, queratinocitos, fibroblastos y médula tímica. También se ha detectado su expresión en linfocitos T
activados. MICA es reconocida por un receptor denominado
NKG2D, que se expresa en células NK y linfocitos T δγ y αβ CD8+.
La expresión de MICA aumenta en respuesta a infecciones o por
neotransformación, desencadenando la citotoxicidad y secreción
de IFN-γ por células que expresan NKG2D. Asimismo, la expresión de MICA en tejidos inflamados o en enfermedades autoinmunes (artritis reumatoidea, enfermedad celíaca y dermatitis seborreica) podría contribuir a la inmunopatología. Se han detectado aloanticuerpos contra MICA en sueros de pacientes transplantados con rechazo del aloinjerto, por lo que MICA es blanco
de una respuesta inmune alogeneica durante el rechazo de un
transplante. Recientemente se ha puesto interés en MICA como
inductor de una respuesta citotóxica anti-tumoral y la secreción
de IFN-γ por células NKG2D+. Sin embargo, nuevas evidencias
indican que algunos tumores desarrollaron mecanismos de escape que comprometen al sistema MICA-NKG2D tales como la
secreción de MICA soluble, la disminución de la expresión de
NKG2D y MICA inducido por el TGF-β de origen tumoral, o la
retención intracelular de MICA, lo que compromete la vigilancia
inmunológica. En esta revisión abordamos estos conceptos en
detalle y resumimos otros conocimientos acerca de la inmunobiología de MICA.
ABSTRACT
The MHC class I chain-related gene A (MICA) encodes for a distantly MHC class I-related polymorphic glycoprotein not associated with β2-microglobulin mainly expressed by epithelial and
non epithelial tumors, gastrointestinal epithelium, freshly isolated human endothelial cells, keratinocytes and fibroblasts, and in
thymic medulla. Expression of MICA also has been observed in
activated T cells. MICA is recognized by the C-type lectin NKG2D
receptor, which is expressed by NK cells, δγ and αβ CD8+ T lymphocytes. MICA expression is up-regulated in response to infection
and neotransformation, resulting in a cytotoxic response and IFNγ secretion mediated by NKG2D-expressing cells. Also, up-regulated expression of MICA under inflammatory conditions and
in autoimmune diseases like rheumatoid arthritis, celiac disease
and seborrhoeic dermatitis, might contribute to the immunopathology of these illnesses. Furthermore, anti-MICA alloantibodies
have been detected in sera of patients who rejected solid organ
transplants, indicating that MICA is a target for an alloimmune
response during solid organ transplantation. Since MICA is widely
expressed on tumors of different histotypes, some interest has
been focused on its capacity to trigger an efficient cytotoxic antitumor immune response and secretion of IFN-γ by NKG2D-expressing cells. However, recent evidence has demonstrated that tumors
developed escape mechanisms that involve the MICA-NKG2D
system like shedding of soluble MICA, tumor-derived TGF-βinduced down-regulation of NKG2D and MICA, and intracellular retention of MICA, which impair the immunosurveillance process. In this review we address these issues in detail and summarize current concepts about the immunobiology of MICA.
PALABRAS CLAVE: MHC/ MICA/ Transplante/ Tumor/
NKG2D/ Células NK.
KEY WORDS: MHC/ MICA/ Transplant/ Tumor/ NKG2D/ NK
cells.
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IMMUNOBIOLOGY OF THE HUMAN MHC CLASS I CHAIN-RELATED GENE A (MICA) ...
INTRODUCTION
The human major histocompatibility complex (MHC)
comprises a cluster of genes mapping to the short arm of
chromosome 6. Most of them encode polypeptides mainly
involved in antigen presentation to T lymphocytes. In 1994,
a new family of polymorphic genes that map within the
MHC class I region was described(1). This family was named
MHC class I chain-related (MIC, Fig. 1), and comprises 2
functional genes (MICA and MICB) and several pseudogenes
MICC to MICF(2). Simultaneously, others described a gene
family that was named PERB11(3), but it was soon realized
that PERB11.1 is MICA and that PERB11.2 is MICB. MICA
has an overall homology of 83% with MICB, but their
homology with the classical MHC class I genes is quite low,
being between 15 and 35%(1).
Typically, MICA encodes for a polypeptide of 383 amino
acids that is expressed on the cell surface of different cells
and resembles the domain organization of the α chain of
MHC class I molecules (one leader peptide encoded by exon
1, three extracellular globular domains encoded by exons
2 to 4, one transmembrane domain encoded by exon 5 and
a cytoplasmic tail encoded by exon 6). However, MICA
does not associate with β2-microglobulin(4, 5). The polypeptide
has a Mr of approximately 42-44 kDa, but the mature protein
has a Mr of ~65kDa. This difference is due to glycosilation
at 8 potential N-glycosilation sites located along the 3
extracellular domains(4). Recently, alternative spliced forms
of MICA lacking exon 3 have been detected(6). Although
these polypeptides can reach the cell surface, it is currently
unknown if they are functional.
The crystal structure of MICA has revealed some unusual
characteristics for a MHC class I-encoded molecule(7). It was
confirmed that MICA does not associate with β2-microglobulin
and it was observed that the putative peptide-binding groove
is too narrow to accommodate a ligand, suggesting that
MICA is not an antigen presenting molecule.
EXPRESSION OF MICA
MICA equivalent genes are present in different species
but not in the mouse genome(1, 8). However, two putative
orthologous genes to MICA and MICB have been described
in the mouse genome(9). Like the other MHC class I genes,
MICA is codominantly expressed(10).
MICA transcripts were first detected in human epithelial
and fibroblast cell lines(1). When antibodies (Ab) against
MICA became available, it was demonstrated that MICA
was expressed by human epithelial and fibroblast cell lines(4,
5, 11), freshly isolated human endothelial cells, and fibroblasts(12),
tumors of different histotypes(13), some melanomas and T
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Figure 1. Map of the human MHC class I region showing the location of the
MIC genes. Classical human MHC class I genes (HLA-A, -B and -C) are
indicated as gray boxes, non-classical MHC class I genes (HLA-E, -F and -G)
are indicated as hatched boxes, the MIC gene family members are indicated
as white boxes, and the TNF gene is indicated as a black box. y is used to indicate
the pseudogenes of the MIC gene family.
cell leukemia cell lines(14), in thymic medulla(15), and in
gastrointestinal epithelium(4). Expression of MICA was also
observed in human keratinocytes (5), which showed no
expression of this molecule on the cell surface(12, 16). The
detection of MICA in tumors suggested that its expression
might be related to the process of neotransformation.
MICA is not expressed by resting T or B lymphocytes,
but PHA-activated CD4+ and CD8+ T cell blasts express
MICA(5). This expression could also be triggered by stimulation
with allogeneic peripheral blood mononuclear cells (PBMCs),
and involves TCR/CD3 engagement and costimulation
through CD28(17), involving different cytoplasmic mediators(18)
and NF-κB (19). These results suggest that MICA can be
induced not only upon neotransformation, but also during
cell activation, two cellular processes coincidentally regulated
by NF-κB(20-23). However, low surface expression of MICA
was observed on activated T lymphocytes(17).
RECOGNITION OF MICA BY NKG2D
After the description that MICA is expressed at the cell
surface(4), research was focused on the identification of its
putative receptor. Initially, it was observed that Vδ1 γδ T
lymphocyte cell lines established from tumor infiltrating
lymphocytes present in tumors of patients with
adenocarcinomas recognize MICA-transfected cells or
MICA-expressing tumor targets, triggering a cytotoxic
response that could be blocked by anti-MICA or anti-γδ
TCR monoclonal Abs (mAbs)(11). However, it was later
demonstrated that the actual receptor for MICA is another
cell surface molecule that belongs to the C-type lectin family
of receptors named NKG2D(24). Since soluble MICA tetramers
can bind to various Vδ1 γδTCRs expressed on transfected
cells(25), it appears that MICA can be engaged by the Vδ1
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γδTCR and by NKG2D. This dual recognition may provide
a fine-tuning to protect the intestinal mucosa from abnormal
activation of Vδ1 γδTCR T cells.
NKG2D is mainly expressed by all human NK cells, δγ
T lymphocytes, and αβ CD8+ T lymphocytes, being a type
II cell surface glycoprotein with a Mr of ~42 kDa that displays
minor homology with other members of the NKG2 family
of receptors. NKG2D is expressed at the cell surface as a
homodimer associated with an adaptor protein called
DAP10(26), which is necessary to elicit the activation of a
specific signal transduction cascade upon engagement of
MICA(27-30).
The crystal structure of the MICA-NKG2D complex has
revealed that NKG2D binds as a homodimer to one molecule
of MICA(31). One of the NKG2D molecules binds mostly
to the α1 domain of MICA, while the other NKG2D molecule
binds mostly to the α2 domain of MICA. The NKG2D
homodimer overlays MICA diagonally in a similar way as
the αβTCR overlays the MHC class I molecules. The central
section of the α2 domain of MICA (residues 152-161),
disordered in the crystal structure of isolated MICA(7), is
ordered when bound to NKG2D and takes part of the
interface between these 2 molecules. It is likely that this
induced fit is promoted by NKG2D. Moreover, the hypothetical
binding pocket of MICA remained free of any ligand,
confirming that MICA is not an antigen-presenting molecule.
The half-life for the MICA-NKG2D complex indicates
that it is more stable than the complexes formed by the TCR
and the MHC class I molecules.
Although it is not our intention to provide a detailed
description of NKG2D since excellent reviews have been
published(28, 32-39), we want to mention that humans and
mice have NKG2D and that this receptor is promiscuous
in terms of ligand recognition. Human NKG2D ligands
(NKG2DLs) are MICA and MICB (40) , and a group of
glycosylphosphatidylinositol (GPI)-bound surface molecules
called UL16 binding protein (ULBP)-1, -2, -3(41) and –4(42).
Mice, which lack the whole MIC gene family, have the
retinoic acid early inducible gene (Rae)-1β (a GPI-anchored,
cell surface glycoprotein), the minor histocompatibility
antigen H60 (an integral transmembrane protein), and the
murine UL16-binding protein-like transcript 1 (MULT-1)(43)
as NKG2DLs. All exhibit low sequence homology with their
human counterparts(44) although human NKG2D binds
mouse NKG2DLs(40) and mouse NKG2D can recognize some
human NKG2DLs (45), most likely reflecting a selective
advantage of preserving the NKG2D receptor in both species
regardless of the recognized ligand.
The MICA-NKG2D system is a versatile ligand-receptor
pair since NKG2D can act as primary receptor or costimulatory
N. WALTER ZWIRNER ET AL.
molecule during anti-tumor immune responses(11,14,25,45,46),
infection(47, 48) or autoimmunity(49, 50). How this dual function
is achieved and regulated is still an open question. In mice,
alternative splicing of NKG2D mRNA leads to two distinct
polypeptides that associate differentially with the DAP10
or DAP12 adaptor proteins and determines whether NKG2D
functions as costimulatory molecule for CD8+ T lymphocytes
or as primary recognition receptor for NK cells(51). However,
these alternative splicing variants and differential association
with DAP10 or DAP12 has not been observed for human
NKG2D.
POLYMORPHISM OF MICA AND ALLELE FREQUENCY
More than 50 alleles of MICA have been described (an
updated list of them can be found at www.anthonynolan.
org.uk/HIG) and linkage disequilibria between alleles of
the MICA locus and of the HLA-B and HLA-C loci was
found(52-54).
Polymorphic regions in the MICA gene are clustered
along exons 2 to 5. Polymorphisms in exons 2 to 4 are
nucleotide substitutions that encode for amino acid
substitutions in the α1, α2 and α3 domains. Conversely,
the polymorphism in exon 5 consists of a different number
of GCT repeats that encode for 4 to 10 Ala residues in the
transmembrane domain. MICA*008 is the most common
allele in North American Caucasoids (allele frequencies
higher than 50%(55, 56)) and the hallmark of this allele is
that, together with MICA*023 and MICA*028, it has an
insertion that generates a premature stop codon in exon
5 which makes the transmembrane domain shorter, and
also lacks the cytoplasmic tail. Besides, the encoded protein
is efficiently expressed at the cell surface(4, 5), where it can
engage NKG2D. Alleles that have this mutation are
aberrantly sorted into polarized cells(57), which may limit
the recognition by NK and γδ T cells during
immunosurveillance in the intestinal epithelium against
infections or neotransformation.
Considering that NKG2D is monomorphic, it is puzzling
why MICA is highly polymorphic. Different MICA alleles
vary in their affinity for NKG2D(40) and these variations
may affect the thresholds of recognition by NK cells and
T lymphocytes. However, there are still no evidences about
the relevance of these affinity differences during cell-cell
interactions, especially considering that most of the
polymorphic residues of MICA do not take part of the
regions involved in the contact with NKG2D. Interestingly,
it has been published that MICA expression is modulated
differentially in cells infected with cytomegalovirus (CMV),
depending on the MICA allele of the target cell(58). Cells with
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the truncated MICA*008 protein maintain MICA expression
at the cell surface, while cells that express other full length
MICA proteins are induced to down-regulate MICA expression
upon CMV infection. Therefore, MICA*008 may promote
the cytolysis of CMV-infected cells and confer resistance to
CMV infection, explaining why this truncated protein is the
most frequent in the population.
MICA IN ORGAN TRANSPLANTATION
Due to its polymorphic nature, it was assumed that
MICA could be a novel transplantation antigen or alloantigen.
Anti-MICA specific Ab were detected in sera of transplant
recipients with different types of rejection episodes(59), these
Ab were absent before the transplant, and they were effectors
of complement mediated cytotoxicity(60). This suggests that
anti-MICA Ab may play a role in solid organ transplantation
outcome most likely by binding to the endothelial cells of
the graft and inducing cell destruction, vascular injury and
organ loss (Fig. 2). Although more work is necessary to
analyze the relevance of these alloantibodies in the rejection
process, their presence correlated with the development of
acute rejection(61). Also, they were are able to bind to kidney
microvascular endothelial cells and to MICA-transfected
cells, fix complement and lyse such target cells and induce
a thrombotic phenotype in endothelial cells. In some cases,
these alloantibodies developed in the absence of anti-MHC
alloantibodies suggesting that anti-MICA alloantibodies
alone may induce rejection.
In addition, renal and pancreatic allografts with acute
or chronic rejection express MICA (62). Since ischemiareperfusion injury induced to a solid organ induces a stress
response in the graft that is associated with the hypoxia and
activation of immune response genes(63, 64), some cytokines
and other proinflammatory mediators induced by the
ischemia-reperfusion may also up-regulate the expression
of MICA on the cell surface of endothelial and stromal cells
of the grafted organ. Although this circuit of ischemiareperfusion injury - proinflammatory cytokines - MICA
expression may trigger graft rejection, studies to establish
the relationship and timing of MICA expression, cellular
infiltration and rejection are necessary to establish the actual
role of MICA during the graft rejection.
Also, it is likely that clinical testing for the presence of
anti-MICA alloantibodies might be implemented to avoid
early rejections. However, the problem would be the source
of the cells to be used in such testing since PBMCs, regularly
used for standard cross-matches for anti-HLA antibodies(65),
do not express MICA(5). Simultaneously, molecular typing
strategies to genotype MICA (3, 52-55, 66-76) may avoid the
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Figure 2. Proposed effects of anti-MICA alloantibodies during solid organ
transplantation. The alloantibodies bind to the endothelial cells of the graft and
trigger effector mechanisms like activation of the complement cascade, Abdependent cellular cytotoxicity mediated by FcRγ expressing cells (ADCC)
and direct toxic effect like induction of thrombosis. The destruction of the
endothelium (vascular injury) in turn promotes the graft disfunction and organ
rejection.
transplantation of MICA-mismatched grafts and lead to a
better graft survival.
Finally, nothing is currently known about the possible
role of MICA (and MICB) in bone marrow transplantation
outcome.
MICA AND INFECTION
Up-regulated MICA expression has been observed in
fibroblasts and endothelial cells upon in vitro infection with
CMV and in vivo in patients with CMV interstitial pneumonia(48,
58), which sensitizes to NKG2D-dependent cytolysis and
IFN-γ secretion by NK cells and CD8+ CD28– αβ T lymphocytes.
Consequently, CMV-driven MICA up-regulation and NKG2Dmediated cytotoxicity of T and NK cells may contribute to
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N. WALTER ZWIRNER ET AL.
Figure 3. Regulated expression of MICA in different situations. Normal cells of different types usually do not express MICA (or express very low levels) but
express MHC class I molecules (center of the figure). Different situations can lead to up-regulation of MICA expression. A) In vitro, it was observed that heat
shock induces MICA on colon adenocarcinoma cells, which triggers a cytotoxic response and IFN-γ secretion by intestinal γδTCR T lymphocytes, contributing to
the lysis of the MICA-expressing cells and to the restoration of the homeostasis of the epithelium. B) During viral infections (CMV), fibroblasts and endothelial
cells up-regulate MICA expression and promote a cytotoxic response mediated by αβTCR CD28–CD8+NKG2D+ T lymphocytes; during Mycobacterium tuberculosis
infection, MICA expression is induced on epithelial and dendritic cells, triggering a cytotoxic response mediated by Vγ2Vδ2 T lymphocytes. In both cases, infected
cells are eliminated and MICA expression contributes to the immunity against these pathogens. C) Activation-induced expression of MICA was also observed in
CD4+ and CD8+ T lymphocytes but this expression remained intracellular. Therefore, the functional consequences of MICA expression in activated T lymphocytes
remain unknown. D) MICA expression is also induced by neotransformation, and tumors that express MICA can be eliminated by NKG2D-expressing cells like
NK cells and CD8+ T lymphocytes, contributing to the immunosurveillance. E) In opposition to these beneficial effects, aberrant expression of MICA was also
observed in enterocytes of the intestinal mucosa of patients with celiac disease, in which IL-15 appears to play an important role. Recognition of MICAexpressing cells by intestinal cytotoxic NKG2D+ lymphocytes appears to contribute to the tissue injury and villous atrophy. Also, synoviocytes of patients with
rheumatoid arthritis aberrantly express MICA. This allows the recognition by CD4+ T lymphocytes that ectopically express NKG2D, most likely induced by IL15 and TNF-α. This recognition leads to the cytotoxicity against the synoviocytes and IFN-γ secretion that contributes to the immunopathology of the joint disease.
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the immunological control of persistent viral infections,
especially considering that MICA appears to be refractory
to the CMV-driven immune escape mechanism that induces
intracellular retention of MICB(77-79). However, other authors
reported that MICA is actually down-regulated upon CMV
infection unless the target cell expresses a truncated allele
protein like MICA*008 that lacks the whole cytoplasmic tail
of the protein(58).
During Hepatitis C virus (HCV) infection, dendritic cells
(DCs) from infected patients were unable to specifically upregulate MICA upon stimulation with IFN-α(80) but did upregulate MICA in response to IL-15(81). This effect contributed
to a poor DC-NK cell cross-talk, and resulted in a dampened
NK cell activation, IFN-γ secretion and cytotoxicity, contributing
to the persistence of HCV infection.
Regarding bacterial infections, infection of epithelial cell
lines and DCs with M. tuberculosis induced up-regulated
expression of MICA and elicited a cytotoxic response and
IFN-γ secretion by Vδ2 γδ T lymphocytes(47). Although the
relevance of this effect in vivo is hard to assess, in one patient
it was observed that MICA expression was detected on DClike cells from a lymph node. Also, epithelial cell lines infected
with Escherichia coli of the diarrheagenic group but not with
other enteroinvasive bacteria, up-regulated MICA on the
cell surface and triggered cytotoxicity and IFN-γ release by
the NKL cell line(82). Hence, MICA is a molecule also involved
in the anti-bacterial immune response.
Accordingly, MICA expression is induced by infectionderived stress or danger signals, triggering a response by
NKG2D-expressing lymphoid cells that leads to the cytolysis
of the infected cells and secretion of IFN-γ. This contributes
to the generation of a pro-inflammatory environment,
promotes the elimination of infected cells, and contributes
to the resolution of the infection and restoration of the
homeostasis (Fig. 3).
MICA AND INFLAMMATORY DISEASES
Unlike MHC class I promoters, the MICA gene lacks the
IFN-γ responsive element(1) and indeed, IFN-γ does not
regulate the expression of MICA(5). However, IL-15(49,50,81,83,84)
and IFN-α(80) up-regulate MICA expression. We observed
up-regulated expression of MICA mRNA in skin biopsies
of patients with seborrhoeic dermatitis that was accompanied
by high levels of mRNA for different proinflammatory
cytokines even in biopsies from areas of the skin without
clinically visible lesions(85), suggesting the existence of an
ongoing inflammation that predisposes healthy skin to
develop overt disease. Although we ignore if the elevated
MICA expression was caused directly by these
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proinflammatory cytokines, these results demonstrate that
some inflammatory conditions are accompanied by upregulated MICA expression in vivo, which may contribute
to the development of tissue injury and the immunopathology
of different diseases.
Anomalous MICA expression was also observed on
synoviocytes from patients with rheumatoid arthritis(49).
Recognition by NKG2D ectopically induced by TNF-α and
IL-15 on CD4+CD28– T lymphocytes induced the proliferation
of auto-aggressive NKG2D+CD4+CD28– T lymphocytes, and
TNF-α and IFN-γ release, contributing to the immunopathology
of the disease. Although the stimuli that induced MICA on
synoviocytes remain unknown, it could be caused by the
proinflammatory environment of the joints.
Patients with active celiac disease with villous atrophy
showed strong MICA expression at the surface of cells from
the surface to the bottom of the crypts(50). MICA was also
expressed in villous epithelial cells of the gut in normal or
disease-free individuals, but this staining was mostly
intracellular. IL-15, which is over-expressed in the intestine
of patients with celiac disease(86-88), appears to be involved
in this up-regulated expression of MICA and contributed
to the cytotoxicity of NKG2D+ intraepithelial lymphocytes
(IELs). These cells lysed epithelial target cell lines in a
NKG2D-dependent way(50, 89), contributing to the villous
atrophy.
Conversely, an anti-inflammatory environment may
contribute to the silencing of the expression of MICA.
Accordingly, suppressing TGF-β production by human
gliomas induced an up-regulation of MICA expression at
the cell surface of the tumors(90).
Therefore, the MICA gene appears to be turned-on in
certain pro-inflammatory environments depending on the
cell type and surrounding cytokines. In some instances, this
expression may be beneficial (clearance of infected cells)
but in other cases (autoimmune diseases) it may be detrimental
for the host. However, the cytokines and pro- and antiinflammatory mediators that regulate MICA expression
need to be further explored in order to be clinically exploited
(Fig. 3).
MICA, DCs, NK CELLS AND T LYMPHOCYTES
Dendritic cells are sentinels of the immune system that
regulate the development of the innate and adaptative
immune response(91). Immature DCs do not express MICA,
but IFN-α and IL-15, while promoting DC maturation, induce
surface expression of MICA(80, 81). Therefore, these cytokines
may participate in the cross-talk of these mature DCs with
NKG2D-expressing cells. Cross talk between NK cells and
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DCs is an important step during the orchestration of the
immune response(92-98). NK cells interact with DCs at sites
of ongoing inflammatory reactions caused by invading
pathogens and in secondary lymphoid organs(98-100), resulting
in cellular activation and development of effector functions.
The NK cell activating receptor NKp30 has been involved
in this cross-talk, but the participation of NKG2D and
recognition of MICA on mature DCs could not be
demonstrated(101, 102).
Most studies about the MICA-NKG2D system have been
performed with NK cells, which constitute a key component
of the innate immune system through their ability to lyse
tumor or virus-infected target cells and provide an early
source of immunoregulatory cytokines. Two populations
of human NK cells have been identified. The major population
(about 90%) is cytotoxic and shows a CD56dimCD16+ phenotype,
whereas the remaining 10% of the NK cells are a source of
immunoregulatory cytokines and present a CD56brightCD16dim
or CD56brightCD16– phenotype(103, 104). Although NKG2D
expression seems to be slightly higher in CD56dim than in
CD56bright NK cells, these differences were not responsible
for the differential IFN-γ production and proliferation of
these NK cell subsets upon interaction with DCs matured
with LPS(97). In addition, it remains unknown if engagement
of NKG2D by MICA or other NKG2DLs on these cell subsets
differentially affects their activation and effector functions,
especially considering that CD56dim NK cells predominate
in peripheral blood, while CD56bright NK cells constitute the
major population of NK cells in secondary lymphoid
organs(99,100,105), interact with DCs and shape the adaptative
immune response(92,93,95,98,103,106-109).
We have demonstrated that expression of MICA can be
induced on CD4+ and CD8+ T lymphocytes upon activation
but were unable to observe a strong surface expression(5,
17-19). Mostly, MICA remained inside the T cell, which may
be a safeguard mechanism to protect activated T cells from
early cytotoxicity by NK cells during a T cell-dependent
immune response in an inflammatory environment, a virusinfected tissue or a tumor microenvironment, where NK
and activated T cells are recruited and further stimulated
with locally produced cytokines. Although activated T
lymphocytes can be killed by NK cells(14, 110), it is possible
that MICA needs an extra signal to become expressed on
the cell surface on activated T cells, produced during the
cross-talk of the activated T lymphocytes with other cell
populations present in inflamed, virus-infected or
neotransformed tissues. A cross-talk of activated CD4+ T
cells and NK cells has been demonstrated recently(111) but
such putative extra signal may also be provided by other
cells present in such tissues. It is possible that activated T
N. WALTER ZWIRNER ET AL.
lymphocytes rapidly express MICA at high levels on the
cell surface by mobilization from intracellular deposits.
Recently, it was observed that MICA can be expressed at
the cell surface on CD8+ T cells stimulated with anti-CD3
or anti-CD3 plus anti-NKG2D mAbs and cultured for 7 days
in the presence of IL-2 or IL-7 plus IL-15(112), but the functional
consequences of this surface expression remain to be elucidated.
We believe that it is advantageous for an activated, effector
T lymphocyte to keep MICA inside the cell, especially in
stressed tissues where high concentrations of IL-15 secreted
by dendritic cells and macrophages induce NKG2D upregulation and cytotoxicity of NK cells against stressed
target cells(50). However, once the termination phase of the
immune response is reached due to antigen exhaustion,
activated T lymphocytes need to be cleared from the body
and surface expression of MICA may contribute to the
elimination of these activated T lymphocytes by NKG2D+
NK cells. The elucidation of the timing of in vivo surface
expression of MICA on T lymphocytes in stressed tissues
will reveal potential strategies to modulate NKG2D-mediated
cytotoxicity mediated by NK cells against activated T
lymphocytes in pathological situations.
MICA IN TUMOR IMMUNOLOGY
Neotransformation is a multi-step process that involves
the accumulation of mutations and a genetic instability that
result in the loss of cell cycle control and the selection of
tumor variants. A novel interpretation of the tumor-host
relationship has lead to the concept of the «cancer
immunoediting»(113, 114). Others propose that tumors simply
generate tumor escape phenotypes during their continuous
growth in the presence of a functional immune system that
imposes an immunological pressure (115). Besides, it is
undisputed that tumors express or up-regulate molecules
that are targets of cytotoxic response mediated by NK and
CD8 T cells, and that an appropriate targeting of the immune
response against such molecules is a crucial event in antitumor immunity.
MICA expression has been observed in different epithelial
and non-epithelial tumor cell lines and freshly isolated
tumors of different histotypes like lung, breast, kidney,
ovary, prostate, colon carcinomas, melanomas and acute
myeloid leukemias, some T-cell acute lymphoblastic leukemias
and multiple myeloma cells(4,5,11,13,14,45,46,116-126). Neo-expression
of MICA appears to be related to the activation of the DNA
damage pathway(127), although the study of the transcription
factors involved in MICA gene expression is an open field
that merits further exploration. Only a few reports about
transcription factors that regulate MICA expression have
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IMMUNOBIOLOGY OF THE HUMAN MHC CLASS I CHAIN-RELATED GENE A (MICA) ...
been published(19, 128). The knowledge of these pathways
may reveal potential targets for immune intervention to
induce efficient cytotoxic anti-tumor immune responses.
Expression of MICA on different tumors promotes
cytolysis and IFN-γ secretion by lymphoid NKG2D-expressing
cells (4,11,14,24,28,30,39,40,45,46,119,121,129-134). NKG2D may act as a
costimulatory molecule or as a primary receptor involved
in target cell recognition. Therefore, it emerges as the major
receptor involved in NK cell mediated lysis of epithelial
and non-epithelial tumors. However, the cytotoxic potential
of the MICA-NKG2D system is counterbalanced by the
interaction of classical and non-classical MHC class I molecules
of the tumor cells through interaction with KIR or other
inhibitory receptors expressed by the NK cells(46).
Despite this overwhelming in vitro evidence, in vivo
evidences about the role of MICA in tumor growth control
and clinical correlations with tumor aggressiveness are not
so abundant. In melanomas, intensity of MICA expression
did not correlate with the Breslow thickness or with the
metastatic capacity(116). In colorectal cancer patients, it was
observed that there is no correlation between clinicopathological
parameters and intensity of MICA expression(135), although
patient survival correlated with levels of MICA expression.
Another study reported that invasive rectal tumors upregulate MICA whereas their levels of expression (mRNA
levels) were lower in early tumors(123). Also, higher levels
of MICA were found on tumor cells of patients with
monoclonal gammopathy of unknown significance, compared
to multiple myeloma cells, indicating that MICA expression
is higher in some pre-neoplastic conditions than on cells of
advanced stage tumors(136). Conversely, results obtained
in our lab showed that benign melanomas (nevus) do not
express MICA but that malign melanoma metastases express
this NKG2DL (Fuertes M.B., unpublished results), which is
in line with previous findings demonstrating MICA expression
by malign melanomas of different degrees(116). Although
these results may look puzzling, they should be interpreted
in light of recent findings demonstrating that sustained
expression of MICA or other NKG2DLs by tumors can elicit
NKG2D down-regulation leading to a defect in NK cellmediated cytotoxicity(118, 122, 130, 137-144). These findings also
conciliate puzzling results showing that MICA and other
NKG2DLs are usually expressed on the surface of many
tumors in immunocompetent hosts, despite the presence of
cytotoxic NKG2D-expressing cells. Such down-regulation
of NKG2D is reversible but imposes a functional impairment
to the immunosurveillance exerted by NK cells and γδ
and αβ CD8+ T lymphocytes(118,126,133,139,142). Surface downregulation of NKG2D is induced by soluble MICA (sMICA),
which in turn derives from metalloprotease-mediated
32
VOL. 25 NUM. 1/ 2006
Figure 4. MICA in tumor immune escape. Most tumors induce surface
expression of MICA as consequence of the neotransformation process. However,
through the secretion of TGF-β they promote down-regulation of MICA
from the cell surface, and through the secretion of tissue metalloproteases
(MMPs), tumors shed soluble MICA (sMICA). Both, TGF-β and sMICA
promote down-regulation of NKG2D from the cell surface of NK cell and CD8+
T lymphocytes. This leads to a deficient recognition of the tumor cells (cytotoxic
effector cells become «blind» to MICA-expressing tumors) leading to a poor
cytotoxic response and IFN-γ secretion, and promoting the tumor immune
escape.
proteolytic shedding from the tumor cell surface.
Metalloproteases are usually involved in tumor progression
and angiogenesis(145, 146), and they appear to be also involved
in MICA cleavage. The presence of sMICA in serum of breast,
lung, ovarian and colon cancer and melanoma patients
impaired not only the cytotoxic response of the NKG2Dexpressing cells, but also their capacity to secrete IFNγ(139). Hence, the shedding of sMICA by tumors constitutes
a novel tumor immune escape mechanism that makes the
cytotoxic cells «blind» to the presence of MICA on the tumor
cells and that explains the low levels of surface MICA on
highly aggressive, end-stage human tumors (Fig. 4).
Additional tumor immune escape mechanisms that affect
the functionality of the NKG2D system also exist. Tumorderived TGF-β induces the down-regulation of NKG2D
from the NK cell surface, leading to an impairment of the
anti-tumor cytotoxic response(90, 147). Therefore, tumor immune
escape is a complex process that goes beyond the known
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INMUNOLOGÍA
capabilities of TGF-β(148, 149), galectin-1(150), FasL(151), and NCRdependent tumor-induced apoptosis of NK cells(152), and
also compromises optimal interaction of the MICA-NKG2D
system. Indeed, we recently described a novel tumor immune
escape mechanism that relays on an intracellular retention
of MICA in some melanomas that confers resistance to
NK cell-mediated cytotoxicity (Fuertes M.B., submitted). It
is likely that different tumors utilize these mechanisms to
differentially subvert the immune system in order to survive
in immunocompetent hosts.
From a therapeutic point of view, interest has been
centered into the possibilities of up-regulating the expression
of NKG2DLs on tumor cells to boost their susceptibility to
cytotoxic cells. Over-expression of Rae1 and H60 (mouse
NKG2DLs) induced an efficient anti-tumor immune response
in vivo(153, 154) and the anti-tumor effects mediated through
NKG2D could be further enhanced by administration of IL21 (155). Over-expression of MICA on gliomas(45) or lung
carcinomas(156) enhanced their sensitivity to NK cell- and
T cell-mediated cytotoxicity in vitro and delayed the tumor
growth in vivo in xenografted mice. However, in light of the
described tumor immune escape mechanisms that compromise
the MICA-NKG2D system, further research is necessary to
fully understand the actual importance of such tumor immune
escape mechanisms in vivo and how to overcome them before
translating these gene therapy strategies to the treatment
of cancer patients. In this regard, we observed that overexpression of MICA on melanomas that retain this molecule
inside the cell not only restored its surface expression but
also conferred susceptibility to NK cell-mediated cytotoxicity
and induced a delayed in vivo growth in a xenogeneic model
(Fuertes M.B., submitted), suggesting that at least some of
the tumor immune escape mechanisms that compromise
optimal signaling of the MICA-NKG2D system can be
overcome by ectopic gene transfer immunotherapies.
Therefore, novel immunotherapies based on the overexpression of MICA may reinforce the weakened anti-tumor
immune response in a tumor-bearing patient and overcome
some tumor immune escape mechanisms.
Concluding remarks
In only 12 years since the MICA gene was described,
substantial progress has been made in the comprehension
of its immunobiology and how this molecule participates
in the fine-tuning of the innate and adaptive immune response.
MICA has been shown to play a role in very different aspects
of the immune response like transplant rejection, immune
response against viruses and intracellular bacteria, inflammation,
homeostasis of epithelia, and immune response against
tumors. The biological function of MICA is achieved through
N. WALTER ZWIRNER ET AL.
interaction with the NKG2D receptor. According to the
experimental evidence, we believe that MICA should be
considered more as a cell homeostasis sensor than a cell stress
sensor, whose up-regulated expression is induced not only
by cell distress but also by strong proliferation and proinflammatory stimuli that disrupt the cellular homeostasis
and elicits a cytotoxicity that eliminates altered cells, contributing
to the restoration of the normal homeostasis. Moreover,
MICA also participates in tumor immune escape mechanisms.
However, there are many open issues that need to be further
investigated. The development and implementation of typing
strategies of MICA alleles for better matching in solid organ
transplantation may improve their outcome. The role of
MICA in bone marrow transplantation should be investigated,
as well as its role in other autoimmune diseases. The
pharmacologic modulation of MICA expression may favor
the development of more effective immune responses against
viral or bacterial infections, or may reduce the tissue
injury observed in many autoimmune diseases. Thus, research
focused on the development of compounds that affect the
expression of MICA is an important forthcoming issue. To
investigate the transcription factors that control MICA gene
expression and design rational immuno or gene therapies
that modulate MICA expression is also important to promote
more effective immune responses against tumors and to
overcome the tumor immune escape mechanisms that involve
the MICA-NKG2D system. Such research areas will provide
novel approaches to improve human health.
ACKNOWLEDGMENTS
We apologize to the authors of many relevant references
not cited because of space limitations. We would like to
thank Dr. Gabriel Rabinovich for his friendship and support,
and for providing an outstading working environment. We
also thank CONICET, ANPCYT, UBA and Fundación
Antorchas for providing the grants with which the experiments
were performed.
N.W.Z. is a member of the Researcher Career of CONICET.
M.B.F., M.V.G. and C.I.D. are postgraduate fellows of
CONICET. L.E.R. holds a fellowship of the ANPCYT.
CORRESPONDENCE TO:
Norberto W. Zwirner, Ph.D.
Laboratorio de Inmunogenética
Hospital de Clínicas «José de San Martín»
Av. Córdoba 2351, 3er piso.
C1120AAF Buenos Aires, Argentina.
Phone: 54-11-5950-8755/8756/8757. Fax: 54-11-5950-8758
E-mail: nwz@sinectis.com.ar
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