Immunobiology of the human MHC class I chain-related gene A (MICA): from transplantation immunology to tumor immune escape
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Inmunol 25/1 10/5/06 17:15 Página 25
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 ABSTRACT
El gen MICA (MHC class I chain-related gene A) codifica para The MHC class I chain-related gene A (MICA) encodes for a dis-
una glicoproteína de superficie distantemente relacionada con las tantly MHC class I-related polymorphic glycoprotein not asso-
moléculas de clase I del CMH. MICA es polimórfica, no se asocia ciated with β2-microglobulin mainly expressed by epithelial and
a β2-microglobulina y se expresa en tumores, epitelio gastroin- non epithelial tumors, gastrointestinal epithelium, freshly isola-
testinal, células endoteliales, queratinocitos, fibroblastos y médu- ted human endothelial cells, keratinocytes and fibroblasts, and in
la tímica. También se ha detectado su expresión en linfocitos T thymic medulla. Expression of MICA also has been observed in
activados. MICA es reconocida por un receptor denominado activated T cells. MICA is recognized by the C-type lectin NKG2D
NKG2D, que se expresa en células NK y linfocitos T δγ y αβ CD8+. receptor, which is expressed by NK cells, δγ and αβ CD8+ T lymp-
La expresión de MICA aumenta en respuesta a infecciones o por hocytes. MICA expression is up-regulated in response to infection
neotransformación, desencadenando la citotoxicidad y secreción and neotransformation, resulting in a cytotoxic response and IFN-
de IFN-γ por células que expresan NKG2D. Asimismo, la expre- γ secretion mediated by NKG2D-expressing cells. Also, up-regu-
sión de MICA en tejidos inflamados o en enfermedades autoin- lated expression of MICA under inflammatory conditions and
munes (artritis reumatoidea, enfermedad celíaca y dermatitis sebo- in autoimmune diseases like rheumatoid arthritis, celiac disease
rreica) podría contribuir a la inmunopatología. Se han detecta- and seborrhoeic dermatitis, might contribute to the immunopat-
do aloanticuerpos contra MICA en sueros de pacientes trans- hology of these illnesses. Furthermore, anti-MICA alloantibodies
plantados con rechazo del aloinjerto, por lo que MICA es blanco have been detected in sera of patients who rejected solid organ
de una respuesta inmune alogeneica durante el rechazo de un transplants, indicating that MICA is a target for an alloimmune
transplante. Recientemente se ha puesto interés en MICA como response during solid organ transplantation. Since MICA is widely
inductor de una respuesta citotóxica anti-tumoral y la secreción expressed on tumors of different histotypes, some interest has
de IFN-γ por células NKG2D+. Sin embargo, nuevas evidencias been focused on its capacity to trigger an efficient cytotoxic anti-
indican que algunos tumores desarrollaron mecanismos de esca- tumor immune response and secretion of IFN-γ by NKG2D-expres-
pe que comprometen al sistema MICA-NKG2D tales como la sing cells. However, recent evidence has demonstrated that tumors
secreción de MICA soluble, la disminución de la expresión de developed escape mechanisms that involve the MICA-NKG2D
NKG2D y MICA inducido por el TGF-β de origen tumoral, o la system like shedding of soluble MICA, tumor-derived TGF-β-
retención intracelular de MICA, lo que compromete la vigilancia induced down-regulation of NKG2D and MICA, and intracellu-
inmunológica. En esta revisión abordamos estos conceptos en lar retention of MICA, which impair the immunosurveillance pro-
detalle y resumimos otros conocimientos acerca de la inmuno- cess. In this review we address these issues in detail and sum-
biología de MICA. marize current concepts about the immunobiology of MICA.
PALABRAS CLAVE: MHC/ MICA/ Transplante/ Tumor/ KEY WORDS: MHC/ MICA/ Transplant/ Tumor/ NKG2D/ NK
NKG2D/ Células NK. cells.
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IMMUNOBIOLOGY OF THE HUMAN MHC CLASS I CHAIN-RELATED GENE A (MICA) ... VOL. 25 NUM. 1/ 2006
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 Figure 1. Map of the human MHC class I region showing the location of the
family that was named PERB11(3), but it was soon realized 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)
that PERB11.1 is MICA and that PERB11.2 is MICB. MICA are indicated as hatched boxes, the MIC gene family members are indicated
has an overall homology of 83% with MICB, but their as white boxes, and the TNF gene is indicated as a black box. y is used to indicate
homology with the classical MHC class I genes is quite low, the pseudogenes of the MIC gene family.
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 cell leukemia cell lines(14), in thymic medulla(15), and in
and resembles the domain organization of the α chain of gastrointestinal epithelium(4). Expression of MICA was also
MHC class I molecules (one leader peptide encoded by exon observed in human keratinocytes (5), which showed no
1, three extracellular globular domains encoded by exons expression of this molecule on the cell surface(12, 16). The
2 to 4, one transmembrane domain encoded by exon 5 and detection of MICA in tumors suggested that its expression
a cytoplasmic tail encoded by exon 6). However, MICA might be related to the process of neotransformation.
does not associate with β2-microglobulin(4, 5). The polypeptide MICA is not expressed by resting T or B lymphocytes,
has a Mr of approximately 42-44 kDa, but the mature protein but PHA-activated CD4+ and CD8+ T cell blasts express
has a Mr of ~65kDa. This difference is due to glycosilation MICA(5). This expression could also be triggered by stimulation
at 8 potential N-glycosilation sites located along the 3 with allogeneic peripheral blood mononuclear cells (PBMCs),
extracellular domains(4). Recently, alternative spliced forms and involves TCR/CD3 engagement and costimulation
of MICA lacking exon 3 have been detected(6). Although through CD28(17), involving different cytoplasmic mediators(18)
these polypeptides can reach the cell surface, it is currently and NF-κB (19). These results suggest that MICA can be
unknown if they are functional. induced not only upon neotransformation, but also during
The crystal structure of MICA has revealed some unusual cell activation, two cellular processes coincidentally regulated
characteristics for a MHC class I-encoded molecule(7). It was by NF-κB(20-23). However, low surface expression of MICA
confirmed that MICA does not associate with β2-microglobulin was observed on activated T lymphocytes(17).
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. 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
EXPRESSION OF MICA putative receptor. Initially, it was observed that Vδ1 γδ T
MICA equivalent genes are present in different species lymphocyte cell lines established from tumor infiltrating
but not in the mouse genome(1, 8). However, two putative lymphocytes present in tumors of patients with
orthologous genes to MICA and MICB have been described adenocarcinomas recognize MICA-transfected cells or
in the mouse genome(9). Like the other MHC class I genes, MICA-expressing tumor targets, triggering a cytotoxic
MICA is codominantly expressed(10). response that could be blocked by anti-MICA or anti-γδ
MICA transcripts were first detected in human epithelial TCR monoclonal Abs (mAbs)(11). However, it was later
and fibroblast cell lines(1). When antibodies (Ab) against demonstrated that the actual receptor for MICA is another
MICA became available, it was demonstrated that MICA cell surface molecule that belongs to the C-type lectin family
was expressed by human epithelial and fibroblast cell lines(4, of receptors named NKG2D(24). Since soluble MICA tetramers
5, 11), freshly isolated human endothelial cells, and fibroblasts(12), can bind to various Vδ1 γδTCRs expressed on transfected
tumors of different histotypes(13), some melanomas and T cells(25), it appears that MICA can be engaged by the Vδ1
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INMUNOLOGÍA N. WALTER ZWIRNER ET AL.
γδTCR and by NKG2D. This dual recognition may provide molecule during anti-tumor immune responses(11,14,25,45,46),
a fine-tuning to protect the intestinal mucosa from abnormal infection(47, 48) or autoimmunity(49, 50). How this dual function
activation of Vδ1 γδTCR T cells. is achieved and regulated is still an open question. In mice,
NKG2D is mainly expressed by all human NK cells, δγ alternative splicing of NKG2D mRNA leads to two distinct
T lymphocytes, and αβ CD8+ T lymphocytes, being a type polypeptides that associate differentially with the DAP10
II cell surface glycoprotein with a Mr of ~42 kDa that displays or DAP12 adaptor proteins and determines whether NKG2D
minor homology with other members of the NKG2 family functions as costimulatory molecule for CD8+ T lymphocytes
of receptors. NKG2D is expressed at the cell surface as a or as primary recognition receptor for NK cells(51). However,
homodimer associated with an adaptor protein called these alternative splicing variants and differential association
DAP10(26), which is necessary to elicit the activation of a with DAP10 or DAP12 has not been observed for human
specific signal transduction cascade upon engagement of NKG2D.
MICA(27-30).
The crystal structure of the MICA-NKG2D complex has
revealed that NKG2D binds as a homodimer to one molecule POLYMORPHISM OF MICA AND ALLELE FREQUENCY
of MICA(31). One of the NKG2D molecules binds mostly More than 50 alleles of MICA have been described (an
to the α1 domain of MICA, while the other NKG2D molecule updated list of them can be found at www.anthonynolan.
binds mostly to the α2 domain of MICA. The NKG2D org.uk/HIG) and linkage disequilibria between alleles of
homodimer overlays MICA diagonally in a similar way as the MICA locus and of the HLA-B and HLA-C loci was
the αβTCR overlays the MHC class I molecules. The central found(52-54).
section of the α2 domain of MICA (residues 152-161), Polymorphic regions in the MICA gene are clustered
disordered in the crystal structure of isolated MICA(7), is along exons 2 to 5. Polymorphisms in exons 2 to 4 are
ordered when bound to NKG2D and takes part of the nucleotide substitutions that encode for amino acid
interface between these 2 molecules. It is likely that this substitutions in the α1, α2 and α3 domains. Conversely,
induced fit is promoted by NKG2D. Moreover, the hypothetical the polymorphism in exon 5 consists of a different number
binding pocket of MICA remained free of any ligand, of GCT repeats that encode for 4 to 10 Ala residues in the
confirming that MICA is not an antigen-presenting molecule. transmembrane domain. MICA*008 is the most common
The half-life for the MICA-NKG2D complex indicates allele in North American Caucasoids (allele frequencies
that it is more stable than the complexes formed by the TCR higher than 50%(55, 56)) and the hallmark of this allele is
and the MHC class I molecules. that, together with MICA*023 and MICA*028, it has an
Although it is not our intention to provide a detailed insertion that generates a premature stop codon in exon
description of NKG2D since excellent reviews have been 5 which makes the transmembrane domain shorter, and
published(28, 32-39), we want to mention that humans and also lacks the cytoplasmic tail. Besides, the encoded protein
mice have NKG2D and that this receptor is promiscuous is efficiently expressed at the cell surface(4, 5), where it can
in terms of ligand recognition. Human NKG2D ligands engage NKG2D. Alleles that have this mutation are
(NKG2DLs) are MICA and MICB (40) , and a group of aberrantly sorted into polarized cells(57), which may limit
glycosylphosphatidylinositol (GPI)-bound surface molecules the recognition by NK and γδ T cells during
called UL16 binding protein (ULBP)-1, -2, -3(41) and –4(42). immunosurveillance in the intestinal epithelium against
Mice, which lack the whole MIC gene family, have the infections or neotransformation.
retinoic acid early inducible gene (Rae)-1β (a GPI-anchored, Considering that NKG2D is monomorphic, it is puzzling
cell surface glycoprotein), the minor histocompatibility why MICA is highly polymorphic. Different MICA alleles
antigen H60 (an integral transmembrane protein), and the vary in their affinity for NKG2D(40) and these variations
murine UL16-binding protein-like transcript 1 (MULT-1)(43) may affect the thresholds of recognition by NK cells and
as NKG2DLs. All exhibit low sequence homology with their T lymphocytes. However, there are still no evidences about
human counterparts(44) although human NKG2D binds the relevance of these affinity differences during cell-cell
mouse NKG2DLs(40) and mouse NKG2D can recognize some interactions, especially considering that most of the
human NKG2DLs (45), most likely reflecting a selective polymorphic residues of MICA do not take part of the
advantage of preserving the NKG2D receptor in both species regions involved in the contact with NKG2D. Interestingly,
regardless of the recognized ligand. it has been published that MICA expression is modulated
The MICA-NKG2D system is a versatile ligand-receptor differentially in cells infected with cytomegalovirus (CMV),
pair since NKG2D can act as primary receptor or costimulatory 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 Figure 2. Proposed effects of anti-MICA alloantibodies during solid organ
transplantation. The alloantibodies bind to the endothelial cells of the graft and
alone may induce rejection. trigger effector mechanisms like activation of the complement cascade, Ab-
In addition, renal and pancreatic allografts with acute dependent cellular cytotoxicity mediated by FcRγ expressing cells (ADCC)
or chronic rejection express MICA (62). Since ischemia- and direct toxic effect like induction of thrombosis. The destruction of the
reperfusion injury induced to a solid organ induces a stress endothelium (vascular injury) in turn promotes the graft disfunction and organ
rejection.
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 transplantation of MICA-mismatched grafts and lead to a
of MICA on the cell surface of endothelial and stromal cells better graft survival.
of the grafted organ. Although this circuit of ischemia- Finally, nothing is currently known about the possible
reperfusion injury - proinflammatory cytokines - MICA role of MICA (and MICB) in bone marrow transplantation
expression may trigger graft rejection, studies to establish outcome.
the relationship and timing of MICA expression, cellular
infiltration and rejection are necessary to establish the actual
role of MICA during the graft rejection. MICA AND INFECTION
Also, it is likely that clinical testing for the presence of Up-regulated MICA expression has been observed in
anti-MICA alloantibodies might be implemented to avoid fibroblasts and endothelial cells upon in vitro infection with
early rejections. However, the problem would be the source CMV and in vivo in patients with CMV interstitial pneumonia(48,
of the cells to be used in such testing since PBMCs, regularly 58), which sensitizes to NKG2D-dependent cytolysis and
used for standard cross-matches for anti-HLA antibodies(65), IFN-γ secretion by NK cells and CD8+ CD28– αβ T lymphocytes.
do not express MICA(5). Simultaneously, molecular typing Consequently, CMV-driven MICA up-regulation and NKG2D-
strategies to genotype MICA (3, 52-55, 66-76) may avoid the mediated cytotoxicity of T and NK cells may contribute to
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INMUNOLOGÍA 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 MICA-
expressing 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 IL-
15 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, proinflammatory cytokines, these results demonstrate that
especially considering that MICA appears to be refractory some inflammatory conditions are accompanied by up-
to the CMV-driven immune escape mechanism that induces regulated MICA expression in vivo, which may contribute
intracellular retention of MICB(77-79). However, other authors to the development of tissue injury and the immunopathology
reported that MICA is actually down-regulated upon CMV of different diseases.
infection unless the target cell expresses a truncated allele Anomalous MICA expression was also observed on
protein like MICA*008 that lacks the whole cytoplasmic tail synoviocytes from patients with rheumatoid arthritis(49).
of the protein(58). Recognition by NKG2D ectopically induced by TNF-α and
During Hepatitis C virus (HCV) infection, dendritic cells IL-15 on CD4+CD28– T lymphocytes induced the proliferation
(DCs) from infected patients were unable to specifically up- of auto-aggressive NKG2D+CD4+CD28– T lymphocytes, and
regulate MICA upon stimulation with IFN-α(80) but did up- TNF-α and IFN-γ release, contributing to the immunopathology
regulate MICA in response to IL-15(81). This effect contributed of the disease. Although the stimuli that induced MICA on
to a poor DC-NK cell cross-talk, and resulted in a dampened synoviocytes remain unknown, it could be caused by the
NK cell activation, IFN-γ secretion and cytotoxicity, contributing proinflammatory environment of the joints.
to the persistence of HCV infection. Patients with active celiac disease with villous atrophy
Regarding bacterial infections, infection of epithelial cell showed strong MICA expression at the surface of cells from
lines and DCs with M. tuberculosis induced up-regulated the surface to the bottom of the crypts(50). MICA was also
expression of MICA and elicited a cytotoxic response and expressed in villous epithelial cells of the gut in normal or
IFN-γ secretion by Vδ2 γδ T lymphocytes(47). Although the disease-free individuals, but this staining was mostly
relevance of this effect in vivo is hard to assess, in one patient intracellular. IL-15, which is over-expressed in the intestine
it was observed that MICA expression was detected on DC- of patients with celiac disease(86-88), appears to be involved
like cells from a lymph node. Also, epithelial cell lines infected in this up-regulated expression of MICA and contributed
with Escherichia coli of the diarrheagenic group but not with to the cytotoxicity of NKG2D+ intraepithelial lymphocytes
other enteroinvasive bacteria, up-regulated MICA on the (IELs). These cells lysed epithelial target cell lines in a
cell surface and triggered cytotoxicity and IFN-γ release by NKG2D-dependent way(50, 89), contributing to the villous
the NKL cell line(82). Hence, MICA is a molecule also involved atrophy.
in the anti-bacterial immune response. Conversely, an anti-inflammatory environment may
Accordingly, MICA expression is induced by infection- contribute to the silencing of the expression of MICA.
derived stress or danger signals, triggering a response by Accordingly, suppressing TGF-β production by human
NKG2D-expressing lymphoid cells that leads to the cytolysis gliomas induced an up-regulation of MICA expression at
of the infected cells and secretion of IFN-γ. This contributes the cell surface of the tumors(90).
to the generation of a pro-inflammatory environment, Therefore, the MICA gene appears to be turned-on in
promotes the elimination of infected cells, and contributes certain pro-inflammatory environments depending on the
to the resolution of the infection and restoration of the cell type and surrounding cytokines. In some instances, this
homeostasis (Fig. 3). 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 anti-
MICA AND INFLAMMATORY DISEASES inflammatory mediators that regulate MICA expression
Unlike MHC class I promoters, the MICA gene lacks the need to be further explored in order to be clinically exploited
IFN-γ responsive element(1) and indeed, IFN-γ does not (Fig. 3).
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 MICA, DCs, NK CELLS AND T LYMPHOCYTES
of patients with seborrhoeic dermatitis that was accompanied Dendritic cells are sentinels of the immune system that
by high levels of mRNA for different proinflammatory regulate the development of the innate and adaptative
cytokines even in biopsies from areas of the skin without immune response(91). Immature DCs do not express MICA,
clinically visible lesions(85), suggesting the existence of an but IFN-α and IL-15, while promoting DC maturation, induce
ongoing inflammation that predisposes healthy skin to surface expression of MICA(80, 81). Therefore, these cytokines
develop overt disease. Although we ignore if the elevated may participate in the cross-talk of these mature DCs with
MICA expression was caused directly by these NKG2D-expressing cells. Cross talk between NK cells and
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INMUNOLOGÍA N. WALTER ZWIRNER ET AL.
DCs is an important step during the orchestration of the lymphocytes rapidly express MICA at high levels on the
immune response(92-98). NK cells interact with DCs at sites cell surface by mobilization from intracellular deposits.
of ongoing inflammatory reactions caused by invading Recently, it was observed that MICA can be expressed at
pathogens and in secondary lymphoid organs(98-100), resulting the cell surface on CD8+ T cells stimulated with anti-CD3
in cellular activation and development of effector functions. or anti-CD3 plus anti-NKG2D mAbs and cultured for 7 days
The NK cell activating receptor NKp30 has been involved in the presence of IL-2 or IL-7 plus IL-15(112), but the functional
in this cross-talk, but the participation of NKG2D and consequences of this surface expression remain to be elucidated.
recognition of MICA on mature DCs could not be We believe that it is advantageous for an activated, effector
demonstrated(101, 102). T lymphocyte to keep MICA inside the cell, especially in
Most studies about the MICA-NKG2D system have been stressed tissues where high concentrations of IL-15 secreted
performed with NK cells, which constitute a key component by dendritic cells and macrophages induce NKG2D up-
of the innate immune system through their ability to lyse regulation and cytotoxicity of NK cells against stressed
tumor or virus-infected target cells and provide an early target cells(50). However, once the termination phase of the
source of immunoregulatory cytokines. Two populations immune response is reached due to antigen exhaustion,
of human NK cells have been identified. The major population activated T lymphocytes need to be cleared from the body
(about 90%) is cytotoxic and shows a CD56dimCD16+ phenotype, and surface expression of MICA may contribute to the
whereas the remaining 10% of the NK cells are a source of elimination of these activated T lymphocytes by NKG2D+
immunoregulatory cytokines and present a CD56brightCD16dim NK cells. The elucidation of the timing of in vivo surface
or CD56brightCD16– phenotype(103, 104). Although NKG2D expression of MICA on T lymphocytes in stressed tissues
expression seems to be slightly higher in CD56dim than in will reveal potential strategies to modulate NKG2D-mediated
CD56bright NK cells, these differences were not responsible cytotoxicity mediated by NK cells against activated T
for the differential IFN-γ production and proliferation of lymphocytes in pathological situations.
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 MICA IN TUMOR IMMUNOLOGY
differentially affects their activation and effector functions, Neotransformation is a multi-step process that involves
especially considering that CD56dim NK cells predominate the accumulation of mutations and a genetic instability that
in peripheral blood, while CD56bright NK cells constitute the result in the loss of cell cycle control and the selection of
major population of NK cells in secondary lymphoid tumor variants. A novel interpretation of the tumor-host
organs(99,100,105), interact with DCs and shape the adaptative relationship has lead to the concept of the «cancer
immune response(92,93,95,98,103,106-109). immunoediting»(113, 114). Others propose that tumors simply
We have demonstrated that expression of MICA can be generate tumor escape phenotypes during their continuous
induced on CD4+ and CD8+ T lymphocytes upon activation growth in the presence of a functional immune system that
but were unable to observe a strong surface expression(5, imposes an immunological pressure (115). Besides, it is
17-19). Mostly, MICA remained inside the T cell, which may undisputed that tumors express or up-regulate molecules
be a safeguard mechanism to protect activated T cells from that are targets of cytotoxic response mediated by NK and
early cytotoxicity by NK cells during a T cell-dependent CD8 T cells, and that an appropriate targeting of the immune
immune response in an inflammatory environment, a virus- response against such molecules is a crucial event in anti-
infected tissue or a tumor microenvironment, where NK tumor immunity.
and activated T cells are recruited and further stimulated MICA expression has been observed in different epithelial
with locally produced cytokines. Although activated T and non-epithelial tumor cell lines and freshly isolated
lymphocytes can be killed by NK cells(14, 110), it is possible tumors of different histotypes like lung, breast, kidney,
that MICA needs an extra signal to become expressed on ovary, prostate, colon carcinomas, melanomas and acute
the cell surface on activated T cells, produced during the myeloid leukemias, some T-cell acute lymphoblastic leukemias
cross-talk of the activated T lymphocytes with other cell and multiple myeloma cells(4,5,11,13,14,45,46,116-126). Neo-expression
populations present in inflamed, virus-infected or of MICA appears to be related to the activation of the DNA
neotransformed tissues. A cross-talk of activated CD4+ T damage pathway(127), although the study of the transcription
cells and NK cells has been demonstrated recently(111) but factors involved in MICA gene expression is an open field
such putative extra signal may also be provided by other that merits further exploration. Only a few reports about
cells present in such tissues. It is possible that activated T transcription factors that regulate MICA expression have
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IMMUNOBIOLOGY OF THE HUMAN MHC CLASS I CHAIN-RELATED GENE A (MICA) ... VOL. 25 NUM. 1/ 2006
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 Figure 4. MICA in tumor immune escape. Most tumors induce surface
patient survival correlated with levels of MICA expression. expression of MICA as consequence of the neotransformation process. However,
Another study reported that invasive rectal tumors up- through the secretion of TGF-β they promote down-regulation of MICA
from the cell surface, and through the secretion of tissue metalloproteases
regulate MICA whereas their levels of expression (mRNA
(MMPs), tumors shed soluble MICA (sMICA). Both, TGF-β and sMICA
levels) were lower in early tumors(123). Also, higher levels promote down-regulation of NKG2D from the cell surface of NK cell and CD8+
of MICA were found on tumor cells of patients with T lymphocytes. This leads to a deficient recognition of the tumor cells (cytotoxic
monoclonal gammopathy of unknown significance, compared effector cells become «blind» to MICA-expressing tumors) leading to a poor
cytotoxic response and IFN-γ secretion, and promoting the tumor immune
to multiple myeloma cells, indicating that MICA expression
escape.
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 proteolytic shedding from the tumor cell surface.
this NKG2DL (Fuertes M.B., unpublished results), which is Metalloproteases are usually involved in tumor progression
in line with previous findings demonstrating MICA expression and angiogenesis(145, 146), and they appear to be also involved
by malign melanomas of different degrees(116). Although in MICA cleavage. The presence of sMICA in serum of breast,
these results may look puzzling, they should be interpreted lung, ovarian and colon cancer and melanoma patients
in light of recent findings demonstrating that sustained impaired not only the cytotoxic response of the NKG2D-
expression of MICA or other NKG2DLs by tumors can elicit expressing cells, but also their capacity to secrete IFN-
NKG2D down-regulation leading to a defect in NK cell- γ(139). Hence, the shedding of sMICA by tumors constitutes
mediated cytotoxicity(118, 122, 130, 137-144). These findings also a novel tumor immune escape mechanism that makes the
conciliate puzzling results showing that MICA and other cytotoxic cells «blind» to the presence of MICA on the tumor
NKG2DLs are usually expressed on the surface of many cells and that explains the low levels of surface MICA on
tumors in immunocompetent hosts, despite the presence of highly aggressive, end-stage human tumors (Fig. 4).
cytotoxic NKG2D-expressing cells. Such down-regulation Additional tumor immune escape mechanisms that affect
of NKG2D is reversible but imposes a functional impairment the functionality of the NKG2D system also exist. Tumor-
to the immunosurveillance exerted by NK cells and γδ derived TGF-β induces the down-regulation of NKG2D
and αβ CD8+ T lymphocytes(118,126,133,139,142). Surface down- from the NK cell surface, leading to an impairment of the
regulation of NKG2D is induced by soluble MICA (sMICA), anti-tumor cytotoxic response(90, 147). Therefore, tumor immune
which in turn derives from metalloprotease-mediated escape is a complex process that goes beyond the known
32Inmunol 25/1 10/5/06 17:15 Página 33
INMUNOLOGÍA N. WALTER ZWIRNER ET AL.
capabilities of TGF-β(148, 149), galectin-1(150), FasL(151), and NCR- interaction with the NKG2D receptor. According to the
dependent tumor-induced apoptosis of NK cells(152), and experimental evidence, we believe that MICA should be
also compromises optimal interaction of the MICA-NKG2D considered more as a cell homeostasis sensor than a cell stress
system. Indeed, we recently described a novel tumor immune sensor, whose up-regulated expression is induced not only
escape mechanism that relays on an intracellular retention by cell distress but also by strong proliferation and pro-
of MICA in some melanomas that confers resistance to inflammatory stimuli that disrupt the cellular homeostasis
NK cell-mediated cytotoxicity (Fuertes M.B., submitted). It and elicits a cytotoxicity that eliminates altered cells, contributing
is likely that different tumors utilize these mechanisms to to the restoration of the normal homeostasis. Moreover,
differentially subvert the immune system in order to survive MICA also participates in tumor immune escape mechanisms.
in immunocompetent hosts. However, there are many open issues that need to be further
From a therapeutic point of view, interest has been investigated. The development and implementation of typing
centered into the possibilities of up-regulating the expression strategies of MICA alleles for better matching in solid organ
of NKG2DLs on tumor cells to boost their susceptibility to transplantation may improve their outcome. The role of
cytotoxic cells. Over-expression of Rae1 and H60 (mouse MICA in bone marrow transplantation should be investigated,
NKG2DLs) induced an efficient anti-tumor immune response as well as its role in other autoimmune diseases. The
in vivo(153, 154) and the anti-tumor effects mediated through pharmacologic modulation of MICA expression may favor
NKG2D could be further enhanced by administration of IL- the development of more effective immune responses against
21 (155). Over-expression of MICA on gliomas(45) or lung viral or bacterial infections, or may reduce the tissue
carcinomas(156) enhanced their sensitivity to NK cell- and injury observed in many autoimmune diseases. Thus, research
T cell-mediated cytotoxicity in vitro and delayed the tumor focused on the development of compounds that affect the
growth in vivo in xenografted mice. However, in light of the expression of MICA is an important forthcoming issue. To
described tumor immune escape mechanisms that compromise investigate the transcription factors that control MICA gene
the MICA-NKG2D system, further research is necessary to expression and design rational immuno or gene therapies
fully understand the actual importance of such tumor immune that modulate MICA expression is also important to promote
escape mechanisms in vivo and how to overcome them before more effective immune responses against tumors and to
translating these gene therapy strategies to the treatment overcome the tumor immune escape mechanisms that involve
of cancer patients. In this regard, we observed that over- the MICA-NKG2D system. Such research areas will provide
expression of MICA on melanomas that retain this molecule novel approaches to improve human health.
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 ACKNOWLEDGMENTS
(Fuertes M.B., submitted), suggesting that at least some of We apologize to the authors of many relevant references
the tumor immune escape mechanisms that compromise not cited because of space limitations. We would like to
optimal signaling of the MICA-NKG2D system can be thank Dr. Gabriel Rabinovich for his friendship and support,
overcome by ectopic gene transfer immunotherapies. and for providing an outstading working environment. We
Therefore, novel immunotherapies based on the over- also thank CONICET, ANPCYT, UBA and Fundación
expression of MICA may reinforce the weakened anti-tumor Antorchas for providing the grants with which the experiments
immune response in a tumor-bearing patient and overcome were performed.
some tumor immune escape mechanisms. 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
Concluding remarks CONICET. L.E.R. holds a fellowship of the ANPCYT.
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 CORRESPONDENCE TO:
in the fine-tuning of the innate and adaptive immune response. Norberto W. Zwirner, Ph.D.
Laboratorio de Inmunogenética
MICA has been shown to play a role in very different aspects
Hospital de Clínicas «José de San Martín»
of the immune response like transplant rejection, immune Av. Córdoba 2351, 3er piso.
response against viruses and intracellular bacteria, inflammation, C1120AAF Buenos Aires, Argentina.
homeostasis of epithelia, and immune response against Phone: 54-11-5950-8755/8756/8757. Fax: 54-11-5950-8758
tumors. The biological function of MICA is achieved through E-mail: nwz@sinectis.com.ar
33Inmunol 25/1 10/5/06 17:15 Página 34
IMMUNOBIOLOGY OF THE HUMAN MHC CLASS I CHAIN-RELATED GENE A (MICA) ... VOL. 25 NUM. 1/ 2006
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