Nonclassical Major Histocompatibility Complex Class Research Articles

Non-Classical MHC Class Ib Molecules and their Receptors–Role in Allogeneic Transplantation of Hematopoietic Stem Cells

HLA-E, HLA-G, and major histocompatibility complex class I-related chain A and B (MICA and MICB) proteins belong to human non-classical Major Histocompatibility Complex (MHC) class Ib molecules. These molecules are well known as powerful modulators of the immune response. The majority of the mentioned proteins interact exclusively with receptors from the CD94/NKG2 c-type lectin family. The peptide-presenting HLA-E molecule is recognized by the NKG2A or NKG2C receptor, triggering a signal cascade leading to inhibition or activation of immune cell activity, respectively. Another member of this family is the NKG2D receptor that interacts with the MICA/B proteins, transducing signals that result in activation of immune cells. This article discusses the current knowledge in regard to the genetic properties and physiological functions of the molecules HLA-E and MICA/B as well as the CD94/NKG2 receptors in the context of the potential role of the signaling pathways they constitute in the outcome of hematopoietic stem cell transplantation. Furthermore, the possible role of HLA-G, also a member of the non-classical MHC class Ib family, is considered.

Non-classical Major Histocompatibility Complex Class Makes a Crucial Contribution to Reproduction in the Dairy Cow

The aim of this study was to evaluate the effect of classical and non-classical major histocompatibility complex (MHC) on the reproduction in the dairy cow. Nine pairs of MHC-I genes were chosen according to their homology and possible function, and their transcription levels in maternal peripheral blood mononuclear cells (PBMCs) from all three trimesters and transcription levels in fetal tissues were compared to evaluate their contributions to cattle reproduction. The results showed that three non-classical genes were variably expressed in PBMCs of pregnant cows. MICB was downregulated in the first and second trimesters (P<0.05), but recovered back to the level in replacement heifers in the last trimester (P>0.05). BoLA-NC1* was upregulated in the first and last trimesters (P<0.001) but no different in the second trimester (P>0.05). BoLA-NC3* was upregulated in all trimesters (P<0.001). On the other hand, MICB was upregulated in fetal ear tissues (P<0.001), and BoLA-NC1* was almost silent in both fetal placenta and ear tissues (P<0.001); however, BoLA-NC3* was upregulated in both the fetal placenta and ear tissues (P<0.001). These results suggested that non-classical gene BoLA-NC1* increased maternal immunity against the fetus, which was inhibited by BoLA-NC3*. BoLA-NC3* also inhibited fetal autoimmunity. Apoptosis of the fetal placenta could reduce itself expressing MICB, and upregulated expression of MICB in ear tissues was favorable for the fetus to escape autoimmunity. On the other hand, downregulated expression of MICB in the fetal placenta allows for placental decoherence from the maternal placentome, which was beneficial to fetus delivery. Although classical genes were expressed differentially, their effects were restricted because of heavy chain deficiency.

Enhancement of the immunosuppressive effect of human adipose tissue-derived mesenchymal stromal cells through HLA-G1 expression

Mesenchymal stromal cells (MSC) from several tissues have immunomodulatory properties that involve various immunosuppressive molecules. An example is human leukocyte antigen (HLA)-G, a non-classical major histocompatibility complex (MHC) class I molecule that induces tolerance via interactions with inhibitory receptors present on major immune effector cells. Recently, the molecular mechanisms that regulate MSC-mediated immunosuppression have come under investigation. Our goal was to determine whether HLA-G plays a crucial role in immunosuppression and whether human adipose tissure (hAT) MSC can be used as a tool for biologic immunosuppression with HLA-G in transplantation. MSC were characterized by fluorescence-activated cell sorting (FACS) analysis, reverse transcriptase (RT)-polymerase chain reaction (PCR) and staining for differentiation. The immunogenicity and immunomodulatory effects of MSC were monitored by peripheral blood mononuclear cell (PBMC) proliferation assay with or without phytohemagglutinin (PHA) stimulation. Stable expression of HLA-G1 in MSC was done using a lentiviral system. Results. MSC from different tissues had similar morphology, immunophenotypic characters and differentiation potential. We also found that the immunosuppressive effect of MSC was monitored along with their endogenous HLA-G mRNA and protein levels. Stable expression of HLA-G1 appeared to enhance the immunosuppressive effect of hAT MSC, and the function of HLA-G1 was significantly decreased by HLA-G antagonistic antibody in PBMC proliferation assays. Although the HLA-G molecule is not the sole factor for MSC-mediated immunosuppression, our data provide evidence that HLA-G plays an important role in immunosuppression and that hAT MSC can be used as a tool for biologic immunosuppression during transplantation procedures.

Surface Expression of HLA-G is Involved in Mediating Immunomodulatory Effects of Placenta-Derived Multipotent Cells (PDMCs) towards Natural Killer Lymphocytes

Interactions between maternal natural killer lymphocytes (NKs) and fetal tissues are important in mediating maternal-fetal tolerance. We therefore investigated the interactions of NKs to placenta-derived multipotent cells (PDMCs) isolated from the term human placenta. PDMCs have similar cell surface marker expression as bone marrow mesenchymal stem cells (BMMSCs) and additionally express human embryonic stem cell markers SSEA-4 and CD-9. Differentiation into the tri-mesodermal lineages of osteoblastic, adipocytic, and chondrogenic phenotypes can be readily achieved under the appropriate conditions. We found that PDMCs are more resistant to NK-mediated lysis than the major histocompatibility complex (MHC) class-I null target cell K562, and can suppress NK secretion of interferon-γ (IFN-γ). Moreover, as third-party cells, PDMCs suppressed the cytotoxic effects of cytokine-stimulated NKs on K562. Pretreatment of PDMCs with IFN-γ, a proinflammatory cytokine, surprisingly enhanced such immunosuppressive effects. Cell-cell contact between NKs and PDMCs is required for suppressive effects, which are partially mediated by slight upregulation of the NK inhibitory receptor killer inhibitory receptor and downregulation of the activating receptor NKp30. Moreover, enhancement of PDMC suppressive effects is also mediated by IFN-γ-induced surface expression of HLA-G--an immunomodulatory nonclassical MHC class I molecule--on PDMCs, as seen by partial reversibility with HLA-G neutralizing antibodies. With its broad immunosuppressive properties, PDMCs may represent a potential cell source for therapeutic use.

Distribution of MICA haplotypes in a Chinese Han population

The MICA gene encodes nonclassical major histocompatibility complex class I molecules, centromeric to HLA-B and telomeric to HLA-DRB1. The MICA genes are polymorphic. The immune response against MICA may correlate with a decrease in graft survival after transplantation. However, data on the frequency of MICA polymorphisms in different populations are limited. In this study, we determined MICA allelic frequencies in a Han population living in Guangdong Province in south China. A total of 15 MICA alleles were identified using sequence-based typing. The most frequent allele was MICA*010 (22.22%), followed by MICA*002:01(18.56%), MICA*008:01(16.32%), and MICA*019(14.93%). The MICA null gene (MICA*Del) exhibited a frequency of 1.743% in this population. MICA and HLA, MICA-HLA-B, and MICA-HLA-A/HLA-B/HLA-DRB1 haplotype frequencies were estimated. The most common 2-, 3- and 4-locus haplotypes were HLA-B*40:01-MICA*008:01 (13.70%), HLA-A*11:01-B*40:01-MICA*008:01(8.25%), and HLA-A*33:03-B*58:01-DRB1*03:01-MICA*002:01(5.22%). A new MICA allele, MICA*061, was identified and appears to be evolutionarily related to MICA*012:01. This study provides high-resolution information on the distribution of haplotypes with MICA, HLA-A, HLA-B, and HLA-DRB1 in China. This information should help determine the mechanisms underlying diseases and allotransplant rejection associated with MICA polymorphisms in the southern Chinese Han population.

A Role for Differential Variable Gene Pairing in Creating T Cell Receptors Specific for Unique Major Histocompatibility Ligands

A limited set of T cell receptor (TCR) variable (V) gene segments are used to create a repertoire of TCRs that recognize all major histocompatibility complex (MHC) ligands within a species. How individual αβTCRs are constructed to specifically recognize a limited set of MHC ligands is unclear. Here we have identified a role for the differential pairing of particular V gene segments in creating TCRs that recognized MHC class II ligands exclusively, or cross-reacted with classical and nonclassical MHC class I ligands. Biophysical and structural experiments indicated that TCR specificity for MHC ligands is not driven by germline-encoded pairwise interactions.Rather, identical TCRβ chains can have altered peptide-MHC (pMHC) binding modes when paired with different TCRα chains. The ability of TCR chain pairing to modify how V region residues interact with pMHC helps to explain how the same V genes are used to create TCRs specific for unique MHC ligands.

Allele frequencies of human leukocyte antigen‐G in a Korean population

The human leukocyte antigen (HLA)-G is a nonclassical major histocompatibility complex class I molecule with relatively limited polymorphism. The differences in allele frequency according to ethnicity and country have not been studied enough, so far. Therefore, fundamental data including allele frequencies and polymorphism are needed for studies on immunological function of HLA-G in each population. We investigated allele frequencies and 14-bp polymorphism of the HLA-G in Koreans. HLA-G alleles and 14-bp polymorphisms were determined by sequence-based typing analysis of exons 2-4 and polymerase chain reaction of exon 8 in 200 unrelated individuals. Genotyping analysis identified eight different HLA-G alleles, which indicates that the Korean population presents limited HLA-G allelic polymorphism. HLA-G*01:01:01:01 and G*01:04:01 were frequent alleles (42.5% and 34.0%), and allelic frequencies were similar to those of other Asian populations. The 14-bp deletion alleles are higher (78%) in Koreans, although the frequencies of the 14-bp insertion/deletion polymorphism have been known to be nearly equal in many Caucasian populations. HLA-G*01:01:08 was reported strong linkage disequilibrium with the 14-bp deletion in a previous report; the same allele was accompanied with 14-bp insertion in our study. There are a few studies investigating allele frequencies, and most of them were studied before high-resolution method era. This is the first study regarding HLA-G genotypes in Korean, which were identified by high-resolution method. From this study, we identified HLA-G frequencies of a Korean population and expect this study could help further investigations for immunological and clinical implications of HLA-G.

Mucosal memory CD8+ T cells are selected in the periphery by an MHC class I molecule

The presence of immune memory at pathogen entry sites is a prerequisite for protection. Nevertheless, the mechanisms that warrant immunity at peripheral interfaces are not understood. Here we show that the non-classical MHC class I molecule, the thymus leukemia antigen (TL), induced on dendritic cells interacting with CD8αα on activated CD8αβ+T cells, mediated affinity-based selection of memory precursor cells. Furthermore, constitutive expression of TL on epithelial cells led to continued selection of mature CD8αβ memory T cells. The TL-CD8αα-driven memory process was essential for the generation of memory CD8αβ T cells in the intestine and accumulation of highly antigen sensitive CD8αβ memory T cells that form the first line of defense at the largest entry port for pathogens.

Soluble Human Leukocyte Antigen-G in Pediatric Renal Transplantation

Soluble Human Leukocyte Antigen-G in Pediatric Renal Transplantation

Human Leukocyte Antigen G Expression in Breast Cancer: Role in Immunosuppression

Human leukocyte antigen G (HLA-G) is an immunotolerant nonclassical major histocompatibility complex Class Ib molecule. It is expressed by trophoblastic placental cells during pregnancy to protect the fetus from maternal alloreactivity. HLA-G is overexpressed in tumors and involved in cancer immune evasion. Reverse transcription-polymerase chain reaction and immunohistochemistry (IHC) were used to examine HLA-G expression in normal mammary and breast cancer cell lines and normal and human breast cancer tissues. Reverse transcription-polymerase chain reaction confirmed that normal epithelial MCF-12A cells had no HLA-G mRNA expression, whereas cancer cell lines MCF-7, T47D, and MDA-MB-231 and NCI/Adr-Res had various levels of HLA-G mRNA expression. Twelve (12) normal and 38 breast cancer tissues were examined by IHC. Fifty-eight (58) percent (22/38) of cancers had medium to strong staining to HLA-G, whereas only 8% (1/12) of normal breast tissues had medium to strong staining, and the difference was significant (p < 0.05). HLA-G staining was found in the membranes and cytoplasm of cancer cells. In conclusion, breast cancer cells overexpress HLA-G mRNA and protein, and this probably contributes to immune evasion.

Expression of HLA-G in patients with hepatocellular carcinoma

Human leukocyte antigen G (HLA-G) is a non-classical major histocompatibility complex class I molecule that has multiple immune regulatory functions including the induction of immune tolerance. The detection of HLA-G expression might serve as a clinical marker in the prediction of clinical outcomes for certain types of carcinoma. Currently, we investigated whether or not HLA-G is also expressed in patients with hepatocellular carcinoma (HCC), and whether the expression has clinical value. Serum levels of secreted HLA-G (sHLA-G) were measured by ELISA in 36 patients with HCC, 25 patients with liver cirrhosis (LC) and 25 healthy individuals. The expression of HLA-G in liver tissue was further studied using Western blotting in 36 patients with HCC and 25 with LC. The correlations between HLA-G status and various clinicopathological parameters including survival were analyzed. The ELISA assay showed that the serum levels of sHLA-G in the HCC, LC and healthy groups were 132.6+/-31.4, 63.5+/-22.1, and 47.0+/-15.5 U/ml, respectively. Analysis of variance was used for inter-group comparison and differences were found between the HCC group and the other two groups (both P<0.01), while no difference was found between the LC group and the healthy group (P=0.112). HLA-G protein expression in liver tissue was found in 66.7% (24/36) of the primary sites of HCC, but not in benign lesions (LC). Further, the HLA-G expression in tumors had no significant correlation with the parameters of age, gender, histological grade and alpha-fetoprotein level. However, patients with HLA-G-positive tumors had a shorter postoperative survival time than those with HLA-G-negative tumors (P=0.014). Also, univariate analysis showed that HLA-G was an independent prognostic factor. Our results indicated that the expression of HLA-G was a characteristic feature of HCC and patients with positive expression of HLA-G in malignant liver tissue had a poor prognosis.

Up-regulation of cytolytic functions of human Vδ2− γδ T lymphocytes through engagement of ILT2 expressed by tumor target cells

AbstractIn humans, the majority of peripheral blood γδ T cells expresses Vγ9Vδ2 T-cell receptors (TCR) and recognize nonpeptidic phosphorylated antigens. In contrast, most tissue-derived γδ T cells, which are located mainly in spleen and epithelia, preferentially use Vδ1 or Vδ3 chains paired with diverse Vγ chains to form their TCR. Our knowledge about the antigenic specificity and costimulation requirements of human Vδ2− γδ T cells remains limited. In an attempt to address this important issue, we characterized the specificity of a monoclonal antibody (mAb 256), screened for its ability to specifically inhibit cytolytic responses of several human Vδ2− γδ T-cell clones against transformed B cells. We show that mAb 256 does not target a TCR ligand but blocks key interactions between non-TCR molecules on effector γδ T cells and ILT2 molecule, expressed by tumor targets. In line with the previously reported specificity of this NK receptor for classic and nonclassic major histocompatibility complex (MHC) class I molecules, blockade of MHC class I/ILT2 interactions using MHC class I- or ILT2-specific mAbs and ILT2-Fc molecules inhibited tumor-induced activation of Vγ8Vδ3 T-cell clones. Therefore, this study describes a new cytotoxic T lymphocyte activation pathway involving MHC class I engagement on γδ T cells.

HLA-G Expression in Cancers: Potential Role in Diagnosis, Prognosis and Therapy

Human leukocyte antigen G (HLA-G) is a non-classic major histocompatibility complex (MHC) class I molecule that functions as an immune suppressive molecule. HLA-G has direct inhibitory effects on natural killer cells(NK), dendritic cells (DC), T cells and has long-term tolerogenic indirect effects by inducing regulator T cells (Treg). HLA-G has been reported to be involved in various physio-pathological conditions such as reproduction, transplantation, autoimmunity, infectious and malignant diseases. In this context, aberrant expression of HLA-G in malignant diseases including hematological and solid tumors has been extensively investigated and its relevance to clinicoparameters and potential significance in diagnosis, prognosis and immune target therapy has been postulated. We here summarized the HLA-G expression in malignancies and emphasis its clinical relevance to malignant disease diagnosis, prognosis, and its potential in target-based immunotherapy was also discussed.

Up‐regulation of HLA‐G expression in cervical premalignant and malignant lesions

The human leukocyte antigen G (HLA-G) molecule, a non-classical major histocompatibility complex class I antigen, exhibits highly limited tissue distribution and gene variation. Recent studies indicate strong immunoinhibitory properties in tumor cells that may favor their escape from anti-tumor immune responses. However, the role of HLA-G in cervical premalignant and malignant lesions has not been defined clearly. In our study, HLA-G expression was studied in cervical tissue from 119 patients with lesions and 22 normal cervical tissue specimens by immunohistochemistry. HLA-G was expressed in 45% (54/119) of cervical lesion-containing tissues while it was rarely detectable (0/22) in the control specimens (P = 0.000). ROC curve analysis showed that HLA-G has an area under the curve (AUC) of 0.694. Furthermore, we investigated soluble HLA-G expression in the plasma of 172 patients with cervical lesions and 20 healthy controls. Significant increases were also observed in soluble HLA-G levels (median, 191.4 vs 45.18 U/ml, P < 0.001). The relative operating characteristic (ROC) curves for soluble HLA-G (sHLA-G), squamous cell carcinoma (SCC), and carbohydrate antigen 125 (CA125) show an AUC of 0.710, 0.634, and 0.588, respectively. At the cut-off values of 108.20 U/ml for sHLA-G, 1.5 ng/ml for SCC, and 35 U/ml for CA125, the sensitivity was 73.30%, 47.83%, and 44.83%, respectively. The detection of soluble HLA-G in plasma may have significance in the early detection of cervical malignant lesions.

Dystrophin conferral using human endothelium expressing HLA-E in the non-immunosuppressive murine model of Duchenne muscular dystrophy.

Human leukocyte antigen (HLA)-E is a non-classical major histocompatibility complex class I (Ib) molecule, which plays an important role in immunosuppression. In this study, we investigated the immunomodulating effect of HLA-E in a xenogeneic system, using human placental artery-derived endothelial (hPAE) cells expressing HLA-E in a mouse model. In vitro cell lysis analysis by primed lymphocytes in combination with siRNA transfection showed that HLA-E is necessary for inhibition of the immune response. Similarly, in vivo cell implantation analysis with siRNA-mediated down-regulation of HLA-E demonstrates that HLA-E is involved in immunosuppression. As hPAE cells efficiently transdifferentiate into myoblasts/myocytes in vitro, we transplanted the cells into mdx mice, a model of Duchenne muscular dystrophy. hPAE cells conferred dystrophin to myocytes of the ‘immunocompetent' mdx mice with extremely high efficiency. These findings suggest that HLA-E-expressing cells with a myogenic potential represent a promising source for cell-based therapy of patients with muscular dystrophy.

γδ T lymphocytes kill T regulatory cells through CD1d

Coxsackievirus B3 (CVB3) induces myocarditis, an inflammation of the myocardium, in C57Bl/6 male mice but not in mice lacking γδ+ T cells [γδ knockout (γδKO)]. Suppression of myocarditis in γδKO mice corresponds to an increase in CD4(+) CD25(+) FoxP3(+) T regulatory cells. A subpopulation of the T regulatory cells in infected γδKO mice expressed high levels of CD1d, a non-classical major histocompatibility complex class 1-like molecule. Adoptive transfer of CD1d(+) and CD1d(-) CD4(+) CD25(+) cells into infected C57Bl/6 recipients showed that the CD1d(+) subpopulation is substantially more suppressive than the CD1d(-) subpopulation. T cells expressing the γδ T-cell receptor comprised approximately 30-50% of the infiltrating lymphoid cells in the hearts of myocarditic C57Bl/6 mice and approximately half of the γδ+ cells expressed the Vγ4 T-cell receptor. The Vγ4+ cells lysed T regulatory cells from γδKO mice but not from wild-type (C57Bl/6) animals. Lysis was inhibited by antibody to CD1d and zVAD-fmk, a pan-caspase inhibitor. The Vγ4-γδ+ cells were not lytic to T regulatory cells and did not promote myocarditis. These results demonstrate that Vγ4+ cells selectively abrogate T regulatory cells through recognition of CD1d expressed on the regulatory cells and caspase-dependent apoptosis.

Soluble HLA-G Inhibits Myeloid Dendritic Cell Function in HIV-1 Infection by Interacting with Leukocyte Immunoglobulin-Like Receptor B2

Dendritic cells represent a specialized class of professional antigen-presenting cells that are responsible for priming and maintaining antigen-specific effector cell responses and regulating immune activation by cytokine secretion. In HIV-1 infection, myeloid dendritic cells are highly dysfunctional, but mechanisms contributing to their functional alterations are not well defined. Here, we show that soluble molecules of the nonclassical major histocompatibility complex class Ib (MHC-Ib) antigen HLA-G are highly upregulated in the plasma during progressive HIV-1 infection, while levels of membrane-bound HLA-G surface expression on dendritic cells, monocytes, and T cells only slightly differ among HIV-1 progressors, HIV-1 elite controllers, and HIV-1-negative persons. These elevated levels of soluble HLA-G in progressive HIV-1 infection likely result from increased secretion of intracellularly stored HLA-G molecules in monocytes and dendritic cells and contribute to a functional disarray of dendritic cells by inhibiting their antigen-presenting properties, while simultaneously enhancing their secretion of proinflammatory cytokines. Interestingly, we observed that these immunoregulatory effects of soluble HLA-G were mainly mediated by interactions with the myelomonocytic HLA class I receptor leukocyte immunoglobulin-like receptor B2 (LILRB2; ILT4), while binding of soluble HLA-G to its alternative high-affinity receptor, LILRB1 (ILT2), appeared to be less relevant for its immunomodulatory functions on dendritic cells. Overall, these results demonstrate a critical role for soluble HLA-G in modulating the functional characteristics of professional antigen-presenting cells in progressive HIV-1 infection and suggest that soluble HLA-G might represent a possible target for immunotherapeutic interventions in HIV-1-infected persons.

Regulation of a Bovine Nonclassical Major Histocompatibility Complex Class I Gene Promoter1

Studies have shown in humans and other species that the major histocompatibility complex class I (MHC-I) region is involved at a number of levels in the establishment and maintenance of pregnancy. The aim of this study was to characterize how a bovine nonclassical MHC-I gene (NC1) is regulated. Initial serial deletion experiments of a 2-kb fragment of the NC1 promoter identified regions with positive regulatory elements in the proximal promoter and evidence for a silencer module(s) further upstream that cooperatively contributed to constitutive NC1 expression. The cytokines interferon tau (IFNT), interferon gamma (IFNG), and interleukin 4 (IL4) significantly increased luciferase expression in NC1 promoter reporter constructs and endogenous NC1 mRNA levels in a bovine endometrial cell line. In addition, IFNG, IL3, IL4, and progesterone significantly increased Day 7 bovine blastocyst NC1 mRNA expression when supplemented during in vitro embryo culture. Site-directed mutagenesis analysis identified a STAT6 binding site that conferred IL4 responsiveness in the NC1 proximal promoter. Furthermore, methylation treatment of the proximal promoter, which contains a CpG island, completely abrogated constitutive NC1 expression. Overall, the findings presented here suggest that constitutive NC1 expression is regulated positively by elements in the proximal promoter, which are further controlled by upstream silencer modules. The promoter is responsive to IFNT, IFNG, and IL4, suggesting possible roles for these cytokines in bovine preimplantation embryo survival and/or maternal-fetal tolerance. Our studies also suggest that methylation of the proximal promoter, in particular, could play a significant role in regulating NC1 expression.

Immune molecules in neurons and glia – implications for synaptic plasticity after nerve lesion

Event Abstract Back to Event Immune molecules in neurons and glia – implications for synaptic plasticity after nerve lesion Staffan Cullheim1* 1 Karolinska institutet, Department of Neuroscience, Sweden There is accumulating evidence that immune molecules are used by neurons and glia in the CNS to modulate synaptic function and plasticity during development and after nerve injury. Spinal motoneurons in rat and mouse constitutively express mRNAs for the major histocompatibility complex (MHC) class I and beta2-microglobulin (beta2m), which is necessary for surface expression of MHC class I. One classical response to lesion of motor axons is the shedding of synapses from the cell surface of severed motoneurons. We have shown that mice lacking the beta2m gene display a more extensive synaptic elimination from the cell bodies of axotomized spinal motoneurons compared with wild-type (WT) mice. This surplus elimination is directed towards synaptic terminals with a putative inhibitory function. (Oliveira et al., Proc Natl Acad Sci USA 101:17843-17848. 2004). The complement system is a part of the innate immune system. Mice lacking complement proteins C1q or C3 exhibit large defects in the organisation of synapses in the development of the retinogeniculate pathway, resembling the picture seen in the absence of MHC class I (Stevens et al., Cell 131:1164-1178. 2007). We therefore studied the synaptic elimination from axotomized motoneurons in mice deficient in C3. In these mice the elimination was much less prominent than in WT animals, which lends support to the idea that complement proteins are ‘tagging’ synapses to be eliminated. Astrocytes and, in particular, microglia have been attributed important roles in the synaptic elimination response after axon lesion. In mice, mRNAs for classical MHC class I (H2-Kb/Db) was upregulated in both motoneurons and microglia after lesion, while non-classical MHC class I (H2-T22) was upregulated only in motoneurons. In contrast, C1q mRNA was upregulated solely in activated microglia, with no neuronal expression. The general pattern of activation, as revealed by GFAP and Iba 1 immunoreactivity for astrocytes and microglia, respectively, did not reveal any major differences between WT animals and mice with gene deletions for MHC class I or complement proteins. We conclude that the effects exerted by the immune molecules are very specific, probably involves glia but are not mirrored by the general activation pattern of glia. Keywords: MHC-class proteins, motoneuron, nerve lesion, plasticity Conference: Karolinska Institutet 200 years anniversary Symposium on Traumatic Injuries in the Nervous System, Stockholm, Sweden, 15 Sep - 16 Sep, 2010. Presentation Type: Presentation Topic: Traumatic Injuries in the Nervous System Citation: Cullheim S (2010). Immune molecules in neurons and glia – implications for synaptic plasticity after nerve lesion. Front. Neurol. Conference Abstract: Karolinska Institutet 200 years anniversary Symposium on Traumatic Injuries in the Nervous System. doi: 10.3389/conf.fneur.2010.56.00018 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 10 Sep 2010; Published Online: 21 Sep 2010. * Correspondence: Prof. Staffan Cullheim, Karolinska institutet, Department of Neuroscience, Stockholm, Sweden, Staffan.Cullheim@ki.se Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Staffan Cullheim Google Staffan Cullheim Google Scholar Staffan Cullheim PubMed Staffan Cullheim Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

The Emerging Role of HLA-E-Restricted CD8+T Lymphocytes in the Adaptive Immune Response to Pathogens and Tumors

Human leukocyte antigen (HLA)-E is a nonclassical major histocompatibility complex (MHC) class I molecule of limited sequence variability that is expressed by most tissues albeit at low levels. HLA-E has been first described as the ligand of CD94/NKG2 receptors expressed mainly by natural killer (NK) cells, thus confining its role to the regulation of NK-cell function. However, recent evidences obtained by our and other groups indicate that HLA-E complexed with peptides can interact with αβ T-cell receptor (TCR) expressed on CD8+ T cells. Although, HLA-E displays a selective preference for nonameric peptides, derived from the leader sequence of various HLA class I alleles, several reports indicate that it can present also “noncanonical” peptides derived from both stress-related and pathogen-associated proteins. Because HLA-E displays binding specificity for innate CD94/NKG2 receptors, as well as all the features of an antigen-presenting molecule, its role in both natural and acquired immune responses has recently been re-evaluated.