HLA-G: An Important Mediator of Maternal-Fetal Immune-Tolerance

Maternal-fetal immune-tolerance occurs throughout the whole gestational trimester, thus a mother can accept a genetically distinct fetus without immunological aggressive behavior. HLA-G, one of the non-classical HLA class I molecules, is restricted-expression at extravillous trophoblast. It can concordantly interact with various kinds of receptors mounted on maternally immune cells residing in the uterus (e.g. CD4+ T cells, CD8+ T cells, natural killer cells, macrophages, and dendritic cells) for maintaining immune homeostasis of the maternal-fetus interface. HLA-G is widely regarded as the pivotal protective factor for successful pregnancies. In the past 20 years, researches associated with HLA-G have been continually published. Indeed, HLA-G plays a mysterious role in the mechanism of maternal-fetal immune-tolerance. It can also be ectopically expressed on tumor cells, infected sites and other pathologic microenvironments to confer a significant local tolerance. Understanding the characteristics of HLA-G in immunologic tolerance is not only beneficial for pathological pregnancy, but also helpful to the therapy of other immune-related diseases, such as organ transplant rejection, tumor migration, and autoimmune disease. In this review, we describe the biological properties of HLA-G, then summarize our understanding of the mechanisms of fetomaternal immunologic tolerance and the difference from transplant tolerance. Furthermore, we will discuss how HLA-G contributes to the tolerogenic microenvironment during pregnancy. Finally, we hope to find some new aspects of HLA-G in fundamental research or clinical application for the future.

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Dichotomy between the induction of suppressor cells and immunologic tolerance by adult thymectomy.

Journal of Experimental Medicine ◽

10.1084/jem.151.3.743 ◽

1980 ◽

Vol 151 (3) ◽

pp. 743-748 ◽

Cited By ~ 20

Author(s):

Y Borel ◽

L Kilham ◽

S E Kurtz ◽

C L Reinisch

Keyword(s):

T Cells ◽

Immune Tolerance ◽

Immune Suppression ◽

Antigenic Determinant ◽

Suppressor Cells ◽

Immunologic Tolerance ◽

Suppressor T Cells ◽

Cellular Mechanisms

Adult thymectomy prevents the development of suppressor T cells without impairing the induction of immunologic tolerance to the same antigenic determinant. This finding demonstrates that the cellular mechanisms underlying immune suppression and immune tolerance are different.

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Faculty Opinions recommendation of Immune tolerance. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725399019.793507728 ◽

2015 ◽

Author(s):

Rachel R Caspi ◽

Sohyun Sophia Jeon

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Immune Tolerance ◽

Self Tolerance ◽

Distinct Role

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MiR-146a regulates regulatory T cells to suppress heart transplant rejection in mice

Cell Death Discovery ◽

10.1038/s41420-021-00534-9 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Jian Lu ◽

Weiwei Wang ◽

Peiyuan Li ◽

Xiaodong Wang ◽

Chao Gao ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Heart Transplant ◽

Transplant Rejection ◽

Mouse Heart ◽

Allograft Survival ◽

Treg Function ◽

Ifn Γ ◽

Heart Transplant Rejection

AbstractRegulatory T cells (Tregs), which characteristically express forkhead box protein 3 (Foxp3), are essential for the induction of immune tolerance. Here, we investigated microRNA-146a (miR-146a), a miRNA that is widely expressed in Tregs and closely related to their homeostasis and function, with the aim of enhancing the function of Tregs by regulating miR-146a and then suppressing transplant rejection. The effect of the absence of miR-146a on Treg function in the presence or absence of rapamycin was detected in both a mouse heart transplantation model and cell co-cultures in vitro. The absence of miR-146a exerted a mild tissue-protective effect by transiently prolonging allograft survival and reducing the infiltration of CD4+ and CD8+ T cells into the allografts. Meanwhile, the absence of miR-146a increased Treg expansion but impaired the ability of Tregs to restrict T helper cell type 1 (Th1) responses. A miR-146a deficiency combined with interferon (IFN)-γ blockade repaired the impaired Treg function, further prolonged allograft survival, and alleviated rejection. Importantly, miR-146a regulated Tregs mainly through the IFN-γ/signal transducer and activator of transcription (STAT) 1 pathway, which is implicated in Treg function to inhibit Th1 responses. Our data suggest miR-146a controls a specific aspect of Treg function, and modulation of miR-146a may enhance Treg efficacy in alleviating heart transplant rejection in mice.

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Amorphous–Crystalline Calcium Phosphate Coating Promotes In Vitro Growth of Tumor-Derived Jurkat T Cells Activated by Anti-CD2/CD3/CD28 Antibodies

Materials ◽

10.3390/ma14133693 ◽

2021 ◽

Vol 14 (13) ◽

pp. 3693

Author(s):

Yurii P. Sharkeev ◽

Ekaterina G. Komarova ◽

Valentina V. Chebodaeva ◽

Mariya B. Sedelnikova ◽

Aleksandr M. Zakharenko ◽

...

Keyword(s):

T Cells ◽

Calcium Phosphate ◽

Biological Effects ◽

Electrical Potential ◽

Biological Properties ◽

Modern Trend ◽

Calcium Phosphate Coating ◽

Jurkat T Cells ◽

Micro Arc Oxidation

A modern trend in traumatology, orthopedics, and implantology is the development of materials and coatings with an amorphous–crystalline structure that exhibits excellent biocopatibility. The structure and physico–chemical and biological properties of calcium phosphate (CaP) coatings deposited on Ti plates using the micro-arc oxidation (MAO) method under different voltages (200, 250, and 300 V) were studied. Amorphous, nanocrystalline, and microcrystalline statesof CaHPO4 and β-Ca2P2O7were observed in the coatings using TEM and XRD. The increase in MAO voltage resulted in augmentation of the surface roughness Ra from 2.5 to 6.5 µm, mass from 10 to 25 mg, thickness from 50 to 105 µm, and Ca/P ratio from 0.3 to 0.6. The electrical potential (EP) of the CaP coatings changed from −456 to −535 mV, while the zeta potential (ZP) decreased from −53 to −40 mV following an increase in the values of the MAO voltage. Numerous correlations of physical and chemical indices of CaP coatings were estimated. A decrease in the ZP magnitudes of CaP coatings deposited at 200–250 V was strongly associated with elevated hTERT expression in tumor-derived Jurkat T cells preliminarily activated with anti-CD2/CD3/CD28 antibodies and then contacted in vitro with CaP-coated samples for 14 days. In turn, in vitro survival of CD4+ subsets was enhanced, with proinflammatory cytokine secretion of activated Jurkat T cells. Thus, the applied MAO voltage allowed the regulation of the physicochemical properties of amorphous–crystalline CaP-coatings on Ti substrates to a certain extent. This method may be used as a technological mechanism to trigger the behavior of cells through contact with micro-arc CaP coatings. The possible role of negative ZP and Ca2+ as effectors of the biological effects of amorphous–crystalline CaP coatings is discussed. Micro-arc CaP coatings should be carefully tested to determine their suitability for use in patients with chronic lymphoid malignancies.

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Synthesis and Cytotoxic Analysis of Novel Myrtenyl Grafted Pseudo-Peptides Revealed Potential Candidates for Anticancer Therapy

Molecules ◽

10.3390/molecules25081911 ◽

2020 ◽

Vol 25 (8) ◽

pp. 1911 ◽

Cited By ~ 1

Author(s):

Odette Concepción ◽

Julio Belmar ◽

Alexander F. de la Torre ◽

Francisco M. Muñiz ◽

Mariano W. Pertino ◽

...

Keyword(s):

T Cells ◽

Cytotoxic Activity ◽

Cell Lines ◽

Cancer Cell ◽

Anticancer Agents ◽

Cd4 T Cells ◽

Dermal Fibroblast ◽

Colon Adenocarcinoma ◽

Cancer Cell Lines ◽

Biological Properties

Myrtenal is a natural monoterpene isolated from essential oils of several plants and their derivates have shown to have several biological properties including cytotoxicity. The cytotoxic activity of these derivates are being investigated for their antitumor effect leading to the development of potential anticancer agents. In this study, novels Myrtenyl grafted pseudo-peptides were designed, synthesized and functionally characterized as possible therapeutic agents for cancer treatment. Thirteen novel Myrtenyl grafted pseudo-peptides were prepared in high atom economy and efficiency by a classic Ugi-4CR and sequential post-modification. Their structures were confirmed by NMR, and ESI-MS, and its cytotoxic activity was evaluated in three cancer cell lines and primary CD4+ T cells at different proliferative cycles. Our results revealed that some of these compounds showed significant cytotoxicity against human gastric, breast and colon adenocarcinoma cells lines, but not against human dermal fibroblast cell line. Moreover, from the thirteen novel myrtenyl synthesized the compound (1R,5S)-N-{[1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-N-[2-(cyclohexylamino)-2–oxoethyl]-6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-carboxamide (3b) proved to be the best candidate in terms of acceptable EC50, and Emax values in cancer cell lines and at inducing cytotoxicity in CD4+ T cells undergoing active proliferation, without affecting non-proliferating T cells. Overall, the synthesis and characterization of our Myrtenyl derivates revealed novel potential anticancer candidates with selective cytotoxic activity.

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Low-dose IL-2 therapy limits the reduction in absolute numbers of circulating regulatory T cells in rheumatoid arthritis

Therapeutic Advances in Musculoskeletal Disease ◽

10.1177/1759720x211011370 ◽

2021 ◽

Vol 13 ◽

pp. 1759720X2110113

Author(s):

Sheng-Xiao Zhang ◽

Jia Wang ◽

Cai-Hong Wang ◽

Rui-Huan Jia ◽

Ming Yan ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

Side Effects ◽

Regulatory T Cells ◽

Disease Activity ◽

Immune Tolerance ◽

Low Dose ◽

Fold Increase ◽

Plain Language ◽

T Subsets

Background: Circulating regulatory T cells (Tregs) are responsible for mediating immune tolerance and maintaining immunological homeostasis. Decreases in Tregs may be involved in the onset of rheumatoid arthritis (RA). Low-dose interleukin-2 (IL-2) has been considered for the treatment of inflammatory diseases mediated by T cells. This study focused on the status of circulating CD4+T subsets and the clinical feasibility of IL-2 therapies in patients with RA. Methods: The subjects included 888 patients with RA and 100 healthy controls (HCs); 233 RA patients received IL-2 treatment with 0.5 million international units (MIU)/day from days 1 through 5. The demographic features, disease activity, and levels of CD4+T cells measured by modified flow cytometry were collected in all RA patients before and after treatment. Results: RA patients had lower absolute Treg counts (but not Th17) compared with HCs, which was associated with disease activity; previously treated RA patients had the fewest circulating Tregs ( p < 0.05). Patients treated with low-dose IL-2 had a three-fold increase in absolute anti-inflammatory Treg counts, as well as a two-fold increase in the other CD4+T subsets. Moreover, post-treatment levels of markers of disease activity in RA patients treated with IL-2 were significantly lower than the baseline values ( p < 0.001), with no apparent side effects. Conclusion: Decreased absolute counts of circulating CD4+T lymphocyte subsets were observed in patients with RA. Circulating Tregs, which mediate immune tolerance, may be involved in the pathogenesis and progression of RA; however, this was ameliorated by low-dose IL-2, without obvious side effects. Plain language summary Low-dose IL-2 treatment for rheumatoid arthritis • Circulating Tregs may be involved in the pathogenesis and progression of RA. • The absolute count of Tregs was significantly correlated with disease activity measures. • Low-dose IL-2 was able to effectively expade Tregs and help for RA patients’ symptoms remission without evaluated side effects.

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Harnessing regulatory T cells for transplant tolerance in the clinic through mTOR inhibition

Current Opinion in Organ Transplantation ◽

10.1097/mot.0b013e32834c237a ◽

2011 ◽

Vol 16 (6) ◽

pp. 606-613 ◽

Cited By ~ 5

Author(s):

Julien Zuber ◽

Olivier Hermine ◽

Lucienne Chatenoud ◽

Christophe Legendre

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Transplant Tolerance ◽

Mtor Inhibition

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Galectin-1 Confers Endometrial Gene Expression and Protein Related to Maternal-Conceptus Immune Tolerance in Cattle

Biology of Reproduction ◽

10.1093/biolre/ioab215 ◽

2021 ◽

Author(s):

Heather L Chaney ◽

Lindsay F Grose ◽

Jeanna M LaBarbara ◽

Adam W Sirk ◽

Alyssa M Blancke ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

Dendritic Cells ◽

Estrous Cycle ◽

Immune Tolerance ◽

Immune Suppression ◽

Carbohydrate Binding ◽

Expression Of Genes ◽

Pregnant Sheep ◽

Carbohydrate Binding Proteins

Abstract Conceptus secretory factors include galectins, a family of carbohydrate binding proteins that elicit cell adhesion and immune suppression by interacting with intracellular and extracellular glycans. In rodents, galectin-1 (LGALS1) promotes maternal-fetal immune tolerance in the decidua through expansion of tolerogenic CD11c+ dendritic cells, increased anti-inflammatory IL-10, and activation of FOXP3+ regulatory T cells (Treg). This study characterized galectin expression in early ruminant conceptuses and endometrium. We also tested the effect of recombinant bovine LGALS1 (rbLGALS1) and progesterone (P4) on endometrial expression of genes and protein related to maternal-fetal immune tolerance in cattle. Elongating bovine and ovine conceptuses expressed several galectins, particularly, LGALS1, LGALS3 and LGALS8. Within bovine endometrium, expression of LGALS3, LGALS7 and LGALS9 was greater on Day 16 of pregnancy compared to the estrous cycle. Within ovine endometrium, LGALS7 was greater during pregnancy compared to the estrous cycle and endometrium of pregnant sheep tended to have greater LGALS9 and LGALS15. Expression of endometrial LGALS4 was less during pregnancy in sheep. Treating bovine endometrium with rbLGALS1 increased endometrial expression of CD11c, IL-10 and FOXP3, within 24 h. Specifically, within caruncular endometrium, both rbLGALS1 and P4 increased FOXP3, suggesting that both ligands may promote Treg expansion. Using IHC, FOXP3+ cells with a leukocyte phenotype were localized to the bovine uterine stratum compactum near the uterine surface and increased in response to rbLGALS1. We hypothesize that galectins have important functions during establishment of pregnancy in ruminants and bovine conceptus LGALS1 and luteal P4 confer mechanisms of maternal-conceptus immune tolerance in cattle.

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