Publications by authors named "Zhongjun Dong"

49 Publications

Declined miR-181a-5p expression is associated with impaired natural killer cell development and function with aging.

Aging Cell 2021 Mar 29:e13353. Epub 2021 Mar 29.

CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.

MicroRNAs (miRNAs) regulate gene expression and thereby influence cell development and function. Numerous studies have shown the significant roles of miRNAs in regulating immune cells including natural killer (NK) cells. However, little is known about the role of miRNAs in NK cells with aging. We previously demonstrated that the aged C57BL/6 mice have significantly decreased proportion of mature (CD27 CD11b ) NK cells compared with young mice, indicating impaired maturation of NK cells with aging. Here, we performed deep sequencing of CD27 NK cells from young and aged mice. Profiling of the miRNome (global miRNA expression levels) revealed that 49 miRNAs displayed a twofold or greater difference in expression between young and aged NK cells. Among these, 30 miRNAs were upregulated and 19 miRNAs were downregulated in the aged NK cells. We found that the expression level of miR-l8la-5p was increased with the maturation of NK cells, and significantly decreased in NK cells from the aged mice. Knockdown of miR-181a-5p inhibited NK cell development in vitro and in vivo. Furthermore, miR-181a-5p is highly conserved in mice and human. MiR-181a-5p promoted the production of IFN-γ and cytotoxicity in stimulated NK cells from both mice and human. Importantly, miR-181a-5p level markedly decreased in NK cells from PBMC of elderly people. Thus, our results demonstrated that the miRNAs profiles in NK cells change with aging, the decreased level of miR-181a-5p contributes to the defective NK cell development and function with aging. This opens new strategies to preserve or restore NK cell function in the elderly.
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http://dx.doi.org/10.1111/acel.13353DOI Listing
March 2021

Full Activation of Kinase Protein Kinase B by Phosphoinositide-Dependent Protein Kinase-1 and Mammalian Target of Rapamycin Complex 2 Is Required for Early Natural Killer Cell Development and Survival.

Front Immunol 2020 9;11:617404. Epub 2021 Feb 9.

School of Medicine and Institute for Immunology, Tsinghua University, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China.

The role of PI3K-mTOR pathway in regulating NK cell development has been widely reported. However, it remains unclear whether NK cell development depends on the protein kinase B (PKB), which links PI3K and mTOR, perhaps due to the potential redundancy of PKB. PKB has two phosphorylation sites, threonine 308 (T308) and serine 473 (S473), which can be phosphorylated by phosphoinositide-dependent protein kinase-1 (PDK1) and mTORC2, respectively. In this study, we established a mouse model in which PKB was inactivated through the deletion of PDK1 and Rictor, a key component of mTORC2, respectively. We found that the single deletion of PDK1 or Rictor could lead to a significant defect in NK cell development, while combined deletion of PDK1 and Rictor severely hindered NK cell development at the early stage. Notably, ectopic expression of myristoylated PKB significantly rescued this defect. In terms of mechanism, in PDK1/Rictor-deficient NK cells, E4BP4, a transcription factor for NK cell development, was less expressed, and the exogenous supply of E4BP4 could alleviate the developmental defect of NK cell in these mice. Besides, overexpression of Bcl-2 also helped the survival of PDK1/Rictor-deficient NK cells, suggesting an anti-apoptotic role of PKB in NK cells. In summary, complete phosphorylation of PKB at T308 and S473 by PDK1 and mTORC2 is necessary for optimal NK cell development, and PKB regulates NK cell development by promoting E4BP4 expression and preventing cell apoptosis.
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http://dx.doi.org/10.3389/fimmu.2020.617404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901528PMC
February 2021

mTORC1 and mTORC2 coordinate early NK cell development by differentially inducing E4BP4 and T-bet.

Cell Death Differ 2021 Jan 18. Epub 2021 Jan 18.

School of Medicine and Institute for Immunology, Tsinghua University, Beijing, 100084, China.

Natural killer (NK) cell development is a multistep process that requires a variety of signals and transcription factors. The lack of mammalian target of rapamycin (mTOR) kinase severely impairs NK cell development in mice. mTOR binds to Raptor and Rictor to form two complexes, mTORC1 and mTORC2, respectively. How mTOR and its two complexes regulate NK cell development is not fully understood. Here, we developed two methods to inactivate mTOR, Raptor, or Rictor in early stage NK cells (using CD122-Cre) or in late-stage NK cells (using Ncr1-Cre). First, we found that when mTOR was deleted by CD122-Cre during and after NK cell commitment, NK cell development was severely impaired, while Ncr1-Cre mediated mTOR deletion slightly affected NK cell terminal differentiation, suggesting that mTOR is essential for early NK cell differentiation. Second, we found that CD122-mediated deletion of Raptor significantly limited the differentiation of CD27CD11b immature NK (iNK) cell into mature NK cells. In contrast, the absence of Rictor significantly interfered with the differentiation of CD27CD11b early iNK cells. Third, Ncr1-mediated deletion of Raptor, rather than Rictor, moderately affected NK cell terminal differentiation. In terms of mechanism, mTORC1 mainly promotes the expression of NK cell-specific transcription factor E4 promoter-binding protein 4 (E4BP4), while both mTORC1 and mTORC2 can enhance the expression of T-bet. Therefore, mTORC1 and mTORC2 subtly coordinate NK cell development by differentially inducing E4BP4 and T-bet.
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http://dx.doi.org/10.1038/s41418-020-00715-6DOI Listing
January 2021

Asparagine enhances LCK signalling to potentiate CD8 T-cell activation and anti-tumour responses.

Nat Cell Biol 2021 01 8;23(1):75-86. Epub 2021 Jan 8.

Tsinghua-Peking Center for Life Sciences, Beijing, China.

Nutrient availability is central for T-cell functions and immune responses. Here we report that CD8 T-cell activation and anti-tumour responses are strongly potentiated by the non-essential amino acid Asn. Increased Asn levels enhance CD8 T-cell activation and effector functions against tumour cells in vitro and in vivo. Conversely, restriction of dietary Asn, ASNase administration or inhibition of the Asn transporter SLC1A5 impairs the activity and responses of CD8 T cells. Mechanistically, Asn does not directly alter cellular metabolic fluxes; it instead binds the SRC-family protein tyrosine kinase LCK and orchestrates LCK phosphorylation at Tyr 394 and 505, thereby leading to enhanced LCK activity and T-cell-receptor signalling. Thus, our findings reveal a critical and metabolism-independent role for Asn in the direct modulation of the adaptive immune response by controlling T-cell activation and efficacy, and further uncover that LCK is a natural Asn sensor signalling Asn sufficiency to T-cell functions.
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http://dx.doi.org/10.1038/s41556-020-00615-4DOI Listing
January 2021

CBP-mediated Wnt3a/β-catenin signaling promotes cervical oncogenesis initiated by Piwil2.

Neoplasia 2021 01 13;23(1):1-11. Epub 2020 Nov 13.

Department of Obstetrics and Gynecology, China-Japan Friendship Hospital, Beijing, China; Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. Electronic address:

Our previous work demonstrated that Piwil2 reactivated by the human papillomavirus oncoproteins E6 and E7 may reprogram somatic cells into tumor-initiating cells (TICs), which contribute to cervical neoplasia lesions. Maintaining the stemness of TICs is critical for the progression of cervical lesions. Here, we determined that canonical Wnt signaling was aberrantly activated in HaCaT cells transfected with lentivirus expressing Piwil2 and in cervical lesion specimens of low-grade squamous intraepithelial lesion, high-grade squamous intraepithelial lesion, and invasive carcinoma. Blocking the β-catenin and CREB binding protein interaction with ICG-001 significantly downregulated the reprogramming factors c-Myc, Nanog, Oct4, Sox2, and Klf4, thus leading to cell differentiation and preventing tumorigenicity in Piwil2-overexpressing HaCaT cells. Similarly, Piwil2 also critically regulated the canonical Wnt signaling pathway in cervical cancer. We further demonstrated that ICG-001 increased cisplatin sensitivity and significantly suppressed tumor growth of cervical cancer alone or in combination with cisplatin both in vitro and in vivo. The β-catenin/ CREB binding protein-mediated transcription activated by Piwil2 is essential for the maintenance of TICs, therefore contributing to the progression of cervical oncogenesis.
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http://dx.doi.org/10.1016/j.neo.2020.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674161PMC
January 2021

Myeloid deletion of phosphoinositide-dependent kinase-1 enhances NK cell-mediated antitumor immunity by mediating macrophage polarization.

Oncoimmunology 2020 06 3;9(1):1774281. Epub 2020 Jun 3.

School of Medicine and Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China.

A large number of heterogeneous macrophages can be observed in solid tumor lesions. Classically activated M1 macrophages are a powerful killer of cancer cells. In contrast, tumor-associated macrophages (TAMs) are often referred to as M2 phenotype and usually impair tumor immunity mediated by cytotoxic lymphocytes, natural killer (NK) cells and CD8 T cells. Therefore, orchestrating M2 to M1 reprogramming will provide a promising approach to tumor immunotherapy. Here we used a PyMT-induced spontaneous breast cancer model in which M2-polarized macrophages were abundant. This M2 phenotype was closely related to tumor progression and immune dysfunction of NK cells and CD8 T cells. We then found that these TAMs showed increased energy expenditure and over-activation of two kinases, Akt and mammalian target of rapamycin (mTOR). Myeloid inactivation of phosphoinositide-dependent kinase-1 (PDK1), the upstream regulator for Akt and mTOR signaling, significantly reduced excessive metabolic activation of macrophages. Notably, the loss of PDK1 significantly led to regression of breast cancer and prevented lung metastasis. Mechanistically, PDK1 deficiency mainly inhibited the activation of mTOR complex 1 (mTORC1), transforming TAMs into M1 phenotype, thereby reversing tumor-related dysfunction of T cells and NK cells. Therefore, targeting PDK1 may be a new approach for M2 macrophage-enriched solid tumor immunotherapy.
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http://dx.doi.org/10.1080/2162402X.2020.1774281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458637PMC
June 2020

PBX1 expression in uterine natural killer cells drives fetal growth.

Sci Transl Med 2020 04;12(537)

Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.

Abundant decidual natural killer (dNK) cells at the maternal-fetal interface are important during early pregnancy. However, functional subsets of dNK cells remain poorly understood. We describe a CD49aPBX homeobox 1 (PBX1) dNK cell subset that promotes fetal development in humans and mice. The expression of PBX1 in dNK cells is up-regulated via the activated AKT1 pathway through the interaction of major histocompatibility complex G with the immunoglobulin-like transcript 2 receptor. PBX1 drives pleiotrophin and osteoglycin transcription in dNK cells, further promoting fetal development. Decreased PBX1 expression or the PBX1 mutant correlated with fetal growth restriction and pregnancy failure in patients with unexplained recurrent spontaneous abortion (URSA). Inactivation of in mouse dNK cells impairs fetal development by decreasing growth-promoting factors from CD49aPBX1 dNK cells. Impairment of PBX1 in dNK cells has positive correlation with URSA pathogenesis and may provide a potential marker for this condition.
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http://dx.doi.org/10.1126/scitranslmed.aax1798DOI Listing
April 2020

PBX1 promotes development of natural killer cells by binding directly to the Nfil3 promoter.

FASEB J 2020 05 19;34(5):6479-6492. Epub 2020 Mar 19.

Hefei National Laboratory for Physical Sciences at Microscale, Division of Molecular Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.

The transcription factor nuclear factor interleukin-3-regulated protein (NFIL3, also called E4BP4) is crucial for commitment of natural killer (NK) cells from common lymphoid progenitors (CLPs). However, the identity of the factor that can regulate NFIL3 directly during the NK-cell development is not known. Here, we reveal that pre-B-cell leukemia transcription factor 1 (PBX1) can upregulate the NFIL3 expression directly. We used conditional knockout mice in which PBX1 in hematopoietic cells was specifically absent. The number of NK-committed progenitor pre-NKP cells and rNKP cells was reduced significantly in the absence of PBX1, which was consistent with NFIL3 deficiency. Also, the NFIL3 expression in NK cells was decreased if PBX1 was absent. We demonstrated that PBX1 was bound directly to the promoter of Nfil3 and facilitated transcription. Upon knockout of the binding site of PBX1 in the Nfil3 promoter, mice showed fewer NK-precursor cells and NK cells, just like that observed in Nfil3 knockout mice. Furthermore, asparagine N286 in the homeodomain of PBX1 controlled the binding of PBX1 to the Nfil3 promoter. Collectively, these findings demonstrate that the transcription factor PBX1 promotes the early development of NK cells by upregulating the Nfil3 expression directly.
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http://dx.doi.org/10.1096/fj.202000121RDOI Listing
May 2020

Regulation of MHC class I-independent NK cell education by SLAM family receptors.

Adv Immunol 2020 13;145:159-185. Epub 2019 Dec 13.

School of Medicine and Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China. Electronic address:

Seven members of signaling lymphocytic activation molecule (SLAM) family receptors (SFRs) are ubiquitously expressed on hematopoietic cells and they play critical roles in immune cell differentiation and activation. The engagement of these receptors transmits intracellular signaling mainly by recruiting SLAM-associated protein (SAP) and its related adaptors, EWS-FLI1-activated transcript-2 (EAT-2) and EAT-2-related transducer (ERT). The critical roles of SFRs and SAP-family adaptors are highlighted by the discovery that SAP is mutated in human X-linked lymphoproliferative (XLP1) disease in which the contact between T and B cells in germinal center and cytotoxic lymphocytes (NK cells and CD8 T cells) function are severely compromised. These immune defects are closely associated with the defective antibody production and the high incidence of lymphoma in the patients with XLP1. In addition to these well-known functions, SLAM-SAP family is involved in NK cell education, a process describing NK cell functional competence. In this chapter, we will mainly discuss these unappreciated roles of SAP-dependent and SAP-independent SFR signaling in regulating MHC-I-independent NK cell education.
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http://dx.doi.org/10.1016/bs.ai.2019.11.006DOI Listing
May 2020

Structure determination of CAMP factor of Mobiluncus curtisii and insights into structural dynamics.

Int J Biol Macromol 2020 May 15;150:1027-1036. Epub 2019 Nov 15.

Hefei National Laboratory for Physical Sciences at Microscale, Laboratory of Structural Immunology, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China; Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China. Electronic address:

Bacterial vaginosis (BV) is a common type of vaginal inflammation caused by a proliferation of pathogenic bacteria, among which Mobiluncus curtisii. In our previous studies on M. curtisii genome, we identified the presence of a genomic fragment encoding a 25 kDa pore-forming toxin, the CAMP factor, which is known to be involved in the synergistic lysis of erythrocytes namely CAMP reaction. However, whether this hypothetical gene product has hemolytic activity is unknown. Moreover, its relative structure and function are not yet solved. Here we found that the M. curtisii CAMP factor is a monomer at pH 4.4 and oligomer at pH > 4.6. Hemolysis assays showed that M. curtisii CAMP factor could lyse sheep red blood cells efficiently in pH 5.4-7.4. Negative staining electron microscope analysis of the CAMP factor revealed ring-like structures at pH above 4.6. Additionally, the crystal structure of M. curtisii CAMP factor, determineded at 1.85 Å resolution, reveals a 5 + 3 helix motif. Further functional analysis suggested that the structural rearrangement of the N-terminal domain might be required for protein function. In conclusion, this structure-function relationship study of CAMP factor provides a new perspective of the M. curtisii role in BV development.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.10.107DOI Listing
May 2020

Concomitant deletion of SLAM-family receptors, NKG2D and DNAM-1 reveals gene redundancy of NK cell activating receptors in NK cell development and education.

J Leukoc Biol 2020 04 15;107(4):561-572. Epub 2019 Nov 15.

School of Medicine and Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China.

NK cells recognize "unwanted" cells using a variety of germline-encoded activating receptors, such as the seven members of signaling lymphocyte activating molecule (SLAM)-family receptors (SFRs), natural killer cell group 2D (NKG2D), and DNAX accessory molecule-1(DNAM-1). Whether these receptors redundantly or synergistically regulate NK cell development and effector function remains poorly understood. By generating mice lacking SFRs, NKG2D, and DNAM-1, separately or in combination, we found that SLAMF6, one of the SFR members, was associated with NK cell differentiation, but its absence had no severe effect on NK cell differentiation and function, likely due to SFR redundancy. Moreover, we revealed that SFRs might work with other NK cell activating receptors in regulating NK cell development and function. We found that SFR deficiency caused an increase in immature NK cell subsets (CD27 CD11b ), and this effect was further augmented by the additional deficiency of NKG2D but not DNAM-1. However, SFR-deficient NK cells exhibited elevated responsiveness against "missing-self" hematopoietic targets, whereas the deletion of either NKG2D or DNAM-1 could partially abrogate the elevated effect of SFR deficiency on NK cell activation. Therefore, our results reveal the complexity of activating receptors in regulating NK cell differentiation and activation, extending our insights into the gene redundancy and compensatory effect of NK cell activating receptors.
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http://dx.doi.org/10.1002/JLB.1MA1019-186RDOI Listing
April 2020

Synergized regulation of NK cell education by NKG2A and specific Ly49 family members.

Nat Commun 2019 11 1;10(1):5010. Epub 2019 Nov 1.

School of Medicine and Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, 100084, China.

Mice lacking MHC class-I (MHC-I) display severe defects in natural killer (NK) cell functional maturation, a process designated as "education". Whether self-MHC-I specific Ly49 family receptors and NKG2A, which are closely linked within the NK gene complex (NKC) locus, are essential for NK cell education is still unclear. Here we show, using CRISPR/Cas9-mediated gene deletion, that mice lacking all members of the Ly49 family exhibit a moderate defect in NK cell activity, while mice lacking only two inhibitory Ly49 members, Ly49C and Ly49I, have comparable phenotypes. Furthermore, the deficiency of NKG2A, which recognizes non-classical MHC-Ib molecules, mildly impairs NK cell function. Notably, the combined deletion of NKG2A and the Ly49 family severely compromises the ability of NK cells to mediate "missing-self" and "induced-self" recognition. Therefore, our data provide genetic evidence supporting that NKG2A and the inhibitory members of Ly49 family receptors synergize to regulate NK cell education.
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http://dx.doi.org/10.1038/s41467-019-13032-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825122PMC
November 2019

Structure determination of the CAMP factor of Streptococcus agalactiae with the aid of an MBP tag and insights into membrane-surface attachment.

Acta Crystallogr D Struct Biol 2019 Aug 31;75(Pt 8):772-781. Epub 2019 Jul 31.

Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei 230027, People's Republic of China.

CAMP factor is a unique α-helical bacterial toxin that is known for its co-hemolytic activity in combination with staphylococcal sphingomyelinase. It was first discovered in the human pathogen Streptococcus agalactiae (also known as group B streptococcus), but homologous genes have been found in many other Gram-positive pathogens. In this study, the efforts that led to the determination of the first structure of a CAMP-family toxin are reported. Initially, it was possible to produce crystals of the native protein which diffracted to near 2.45 Å resolution. However, a series of technical obstacles were encountered on the way to structure determination. Over a period of more than five years, many methods, including selenomethionine labeling, mutations, crystallization chaperones and heavy-atom soaking, were attempted, but these attempts resulted in limited progress. The structure was finally solved using a combination of iodine soaking and molecular replacement using the crystallization chaperone maltose-binding protein (MBP) as a search model. Analysis of native and MBP-tagged CAMP-factor structures identified a conserved interaction interface in the C-terminal domain (CTD). The positively charged surface may be critical for binding to acidic ligands. Furthermore, mutations on the interaction interface at the CTD completely abolished its co-hemolytic activities. This study provides novel insights into the mechanism of the membrane-permeabilizing activity of CAMP factor.
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http://dx.doi.org/10.1107/S205979831901057XDOI Listing
August 2019

NK cell recognition of hematopoietic cells by SLAM-SAP families.

Cell Mol Immunol 2019 05 25;16(5):452-459. Epub 2019 Mar 25.

Institute for Immunology and School of Medicine, Beijing Key Lab for Immunological Research on Chronic Diseases, 100084, Beijing, China.

The signaling lymphocyte activation molecule (SLAM) family of receptors (SFRs) are ubiquitously expressed on immune cells, and they regulate multiple immune events by recruiting SH2 (Src homology 2) domain-containing SAP family adapters, including SAP and its homologs, Ewing's sarcoma-associated transcript 2 (EAT-2) and EAT-2 related transducer (ERT). In human patients with X-linked lymphoproliferative (XLP) disease, which is caused by SAP mutations, SFRs alternatively bind other inhibitory SH2 domain-containing molecules to suppress immune cell activation and development. NK cells express multiple SFRs and all SAP family adapters. In recent decades, SFRs have been found to be critical for enhancing NK cell activation in response to abnormal hematopoietic cells in SAP-family-intact NK cells; however, SFRs might suppress NK cell activation in SAP-family-deficient mice or patients with XLP1. In this paper, we review how these two distinct SFR signaling pathways orchestrate NK cell activation and inhibition and highlight the importance of SFR regulation of NK cell biology and their physiological status and pathological relevance in patients with XLP1.
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http://dx.doi.org/10.1038/s41423-019-0222-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474203PMC
May 2019

Absence of GdX/UBL4A Protects against Inflammatory Diseases by Regulating NF-кB Signaling in Macrophages and Dendritic Cells.

Theranostics 2019 14;9(5):1369-1384. Epub 2019 Feb 14.

State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, Beijing (100084), China.

Nuclear factor-kappa B (NF-κB) activation is critical for innate immune responses. However, cellular-intrinsic regulation of NF-κB activity during inflammatory diseases remains incompletely understood. Ubiquitin-like protein 4A (UBL4A, GdX) is a small adaptor protein involved in protein folding, biogenesis and transcription. Yet, whether GdX has a role during innate immune response is largely unknown. To investigate the involvement of GdX in innate immunity, we challenged GdX-deficient mice with lipopolysaccharides (LPS). To investigate the underlying mechanism, we performed RNA sequencing, real-time PCR, ELISA, luciferase reporter assay, immunoprecipitation and immunoblot analyses, flow cytometry, and structure analyses. To investigate whether GdX functions in inflammatory bowel disease, we generated dendritic cell (DC), macrophage (Mφ), epithelial-cell specific GdX-deficient mice and induced colitis with dextran sulfate sodium. GdX enhances DC and Mφ-mediated innate immune defenses by positively regulating NF-κB signaling. GdX-deficient mice were resistant to LPS-induced endotoxin shock and DSS-induced colitis. DC- or Mφ- specific GdX-deficient mice displayed alleviated mucosal inflammation. The production of pro-inflammatory cytokines by GdX-deficient DCs and Mφ was reduced. Mechanistically, we found that tyrosine-protein phosphatase non-receptor type 2 (PTPN2, TC45) and protein phosphatase 2A (PP2A) form a complex with RelA (p65) to mediate its dephosphorylation whereas GdX interrupts the TC45/PP2A/p65 complex formation and restrict p65 dephosphorylation by trapping TC45. Our study provides a mechanism by which NF-κB signaling is positively regulated by an adaptor protein GdX in DC or Mφ to maintain the innate immune response. Targeting GdX could be a strategy to reduce over-activated immune response in inflammatory diseases.
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http://dx.doi.org/10.7150/thno.32451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401509PMC
January 2020

Liver-Resident NK Cells Control Antiviral Activity of Hepatic T Cells via the PD-1-PD-L1 Axis.

Immunity 2019 02 29;50(2):403-417.e4. Epub 2019 Jan 29.

Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China; Institue of Immunology, University of Science and Technology of China, Hefei, Anhui 230027, China. Electronic address:

The tolerogenic microenvironment of the liver is associated with impaired hepatic T cell function. Here, we examined the contribution of liver-resident natural killer (LrNK) cells, a prominent hepatic NK cell compartment, to T cell antiviral responses in the liver. The number of virus-specific T cells increased in LrNK-cell-deficient mice during both acute and chronic lymphocytic choriomeningitis virus infection. Upon infection with adenovirus, hepatic T cells from these mice produced more cytokines, which was accompanied by reduced viral loads. Transfer of LrNK cells into LrNK-cell-deficient or wild-type mice inhibited hepatic T cell function, resulting in impaired viral clearance, whereas transfer of conventional NK cells promoted T cell antiviral responses. LrNK-cell-mediated inhibition of T cell function was dependent on the PD-1-PD-L1 axis. Our findings reveal a role for LrNK cells in the regulation of T cell immunity and provide insight into the mechanisms of immune tolerance in the liver.
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http://dx.doi.org/10.1016/j.immuni.2018.12.024DOI Listing
February 2019

Stage-specific requirement of kinase PDK1 for NK cells development and activation.

Cell Death Differ 2019 10 8;26(10):1918-1928. Epub 2019 Jan 8.

School of Medicine and Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, 100084, China.

Phosphoinositide-dependent kinase-1 (PDK1) is an important enzyme for immune cell development by connecting PI3K to downstream mTOR signaling. It is needed to investigate how PDK1 spatiotemporally orchestrates NK cells development and whether this kinase is required for NK cells effector function. In this study, we used three genetic models to delete pdk1 at respective developmental stages, including hematopoietic stem cells (Vav1-Cre used), NK cell progenitor (NKp, CD122-Cre used) and terminal NK cells (Ncr1-Cre used). We found that CD122-Cre mediated deletion of pdk1 caused a severe loss of NK cells to an extent comparable to that of deletion by Vav1-Cre, and further revealed that PDK1 was necessary for NK cells master transcription factor E4BP4 expression at the NKp stage. Moreover, Ncr1-Cre-mediated inactivation of pdk1 delayed NK cells terminal differentiation. These PDK1-deficient NK cells secreted decreased amounts of the cytokine IFN-γ, likely due to impaired downstream mTOR activation. They also exhibited reduced degranulation in response to tumor cells. Mechanistically, PDK1 was critical for the formation of NK-target conjugates and lytic synapses. Therefore, we clarify the stage-specific roles of the metabolic regulator PDK1 in NK cells biology.
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http://dx.doi.org/10.1038/s41418-018-0263-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748128PMC
October 2019

Combined deficiency of SLAMF8 and SLAMF9 prevents endotoxin-induced liver inflammation by downregulating TLR4 expression on macrophages.

Cell Mol Immunol 2020 02 14;17(2):153-162. Epub 2018 Dec 14.

Institute for Immunology and School of Medicine, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, 100086, Beijing, China.

Classical signaling lymphocyte activating molecule (SLAM) family receptors are abundant within many types of immune cells, whereas the nonclassical SLAM family receptors SLAMF8 and SLAMF9, which uniquely lack cytoplasmic signaling motifs, are highly expressed by myeloid cells. Due to the potential redundancy, whether these two receptors regulate macrophage function remains largely unknown. Here, we show that SLAMF8 and SLAMF9 co-regulate macrophage-mediated liver inflammation. To overcome the redundancy, we generated mice that simultaneously lacked SLAMF8 and SLAMF9 using CRISPR-Cas9 technology. Although macrophage differentiation was not altered by the combined deficiency of SLAMF8 and SLAMF9, the loss of these two receptors significantly protected against lipopolysaccharide (LPS)-induced liver injury. SLAMF8 and SLAMF9 double-deficient mice had a prolonged survival rate and less infiltration of inflammatory cells. The depletion of macrophages using clodronate liposomes abolished the effects of SLAMF8 and SLAMF9 deficiencies on LPS-induced liver injury, which demonstrates that these receptors are required for macrophage activation following LPS challenge. Moreover, the deficiency of SLAMF8 and SLAMF9 suppressed the secretion of inflammatory cytokines by downregulating the expression of Toll-like receptor-4 (TLR4), a receptor that specifically binds LPS, which led to decreased mitogen-activated protein kinases (MAPK) signaling activation. Notably, combined injections of truncated extracellular SLAMF8 and SLAMF9 proteins significantly alleviated LPS-induced liver injury. Thus, our findings provide insights into the role of SLAMF8 and SLAMF9 in endotoxin-induced liver injury and suggest that SLAMF8 and SLAMF9 are potential therapeutic targets for acute hepatic injury.
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http://dx.doi.org/10.1038/s41423-018-0191-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000402PMC
February 2020

BLT1 in dendritic cells promotes Th1/Th17 differentiation and its deficiency ameliorates TNBS-induced colitis.

Cell Mol Immunol 2018 12 18;15(12):1047-1056. Epub 2018 Apr 18.

Putuo District People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.

Leukotriene B4 (LTB4) synthesis is enhanced in the colonic mucosa in patients with inflammatory bowel disease (IBD). BLT1, a high-affinity receptor for LTB4, exhibits no effect on the progression of dextran sodium sulfate (DSS)-induced colitis, which mostly relies on innate immunity. Here, we reported that BLT1 regulates trinitrobenzene sulfonic acid (TNBS)-induced colitis, which reflects CD4 T-cell-dependent adaptive immune mechanisms of IBD. We found that BLT1 signaling enhanced the progression of colitis through controlling the production of proinflammatory cytokines by dendritic cells (DCs) and modulating the differentiation of Th1 and Th17. BLT1 mice displayed an alleviated severity of TNBS-induced colitis with reduced body weight loss and infiltrating cells in the lamina propria. BLT1 deficiency in DCs led to reduced production of proinflammatory cytokines, including IL-6, TNF-α, and IL-12, and these results were further confirmed via treatment with a BLT1 antagonist. The impaired cytokine production by BLT1 DCs subsequently led to reduced Th1 and Th17 differentiation both in vitro and in vivo. We further performed a conditional DC reconstitution experiment to assess whether BLT1 in DCs plays a major role in regulating the pathogenesis of TNBS-induced colitis, and the results indicate that BLT1 deficiency in DCs also significantly reduces disease severity. The mechanistic study demonstrated that BLT1-regulated proinflammatory cytokine production through the Gαi βγ subunit-phospholipase Cβ (PLCβ)-PKC pathway. Notably, we found that treatment with the BLT1 antagonist also reduced the production of proinflammatory cytokines by human peripheral blood DCs. Our findings reveal the critical role of BLT1 in regulating adaptive immunity and TNBS-induced colitis, which further supports BLT1 as a potential drug target for adaptive immunity-mediated IBD.
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http://dx.doi.org/10.1038/s41423-018-0030-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269524PMC
December 2018

PTEN-Regulated AID Transcription in Germinal Center B Cells Is Essential for the Class-Switch Recombination and IgG Antibody Responses.

Front Immunol 2018 28;9:371. Epub 2018 Feb 28.

MOE Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Life Sciences, Institute for Immunology, Tsinghua University, Beijing, China.

Class-switch recombination (CSR) and somatic hypermutation (SHM) occur during the differentiation of germinal center B cells (GCBs). Activation-induced cytidine deaminase (AID) is responsible for both CSR and SHM in GCBs. Here, we show that ablation of PTEN through the Cγ1-Cre mediated recombination significantly influences the CSR and SHM responses. The GCs fail to produce the IgG1 B cells, the high affinity antibodies and nearly lost the dark zone (DZ) in mice after immunization, suggesting the impaired GC structure. Further mechanistic investigations show that LPS- and interleukin-4 stimulation induced the transcription of Cγ1 in IgM-BCR expressing B cells, which efficiently disrupts PTEN transcription, results in the hyperphosphorylated AKT and FoxO1 and in turn the suppression of AID transcription. Additionally, the reduced transcription of PTEN and AID is also validated by investigating the IgM-BCR expressing GCBs from mice upon immunization. In conclusion, PTEN regulated AID transcription in GCBs is essential for the CSR and IgG antibody responses.
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http://dx.doi.org/10.3389/fimmu.2018.00371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835858PMC
April 2019

Natural Killer Cells Promote Fetal Development through the Secretion of Growth-Promoting Factors.

Immunity 2017 12;47(6):1100-1113.e6

Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Science and Medical Center, University of Science and Technology of China, Hefei, Anhui 230001, China; Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230001, China. Electronic address:

Natural killer (NK) cells are present in large populations at the maternal-fetal interface during early pregnancy. However, the role of NK cells in fetal growth is unclear. Here, we have identified a CD49aEomes subset of NK cells that secreted growth-promoting factors (GPFs), including pleiotrophin and osteoglycin, in both humans and mice. The crosstalk between HLA-G and ILT2 served as a stimulus for GPF-secreting function of this NK cell subset. Decreases in this GPF-secreting NK cell subset impaired fetal development, resulting in fetal growth restriction. The transcription factor Nfil3, but not T-bet, affected the function and the number of this decidual NK cell subset. Adoptive transfer of induced CD49aEomes NK cells reversed impaired fetal growth and rebuilt an appropriate local microenvironment. These findings reveal properties of NK cells in promoting fetal growth. In addition, this research proposes approaches for therapeutic administration of NK cells in order to reverse restricted nourishments within the uterine microenvironment during early pregnancy.
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http://dx.doi.org/10.1016/j.immuni.2017.11.018DOI Listing
December 2017

Dissection of SAP-dependent and SAP-independent SLAM family signaling in NKT cell development and humoral immunity.

J Exp Med 2017 02 3;214(2):475-489. Epub 2017 Jan 3.

Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100086, China

Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) mutations in X-linked lymphoproliferative disease (XLP) lead to defective NKT cell development and impaired humoral immunity. Because of the redundancy of SLAM family receptors (SFRs) and the complexity of SAP actions, how SFRs and SAP mediate these processes remains elusive. Here, we examined NKT cell development and humoral immunity in mice completely deficient in SFR. We found that SFR deficiency severely impaired NKT cell development. In contrast to SAP deficiency, SFR deficiency caused no apparent defect in follicular helper T (T) cell differentiation. Intriguingly, the deletion of SFRs completely rescued the severe defect in T cell generation caused by SAP deficiency, whereas SFR deletion had a minimal effect on the defective NKT cell development in SAP-deficient mice. These findings suggest that SAP-dependent activating SFR signaling is essential for NKT cell selection; however, SFR signaling is inhibitory in SAP-deficient T cells. Thus, our current study revises our understanding of the mechanisms underlying T cell defects in patients with XLP.
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http://dx.doi.org/10.1084/jem.20161312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294859PMC
February 2017

IL-17C/IL-17RE Augments T Cell Function in Autoimmune Hepatitis.

J Immunol 2017 01 12;198(2):669-680. Epub 2016 Dec 12.

Institute for Immunology, Tsinghua University, Beijing 100084, China;

Autoimmune hepatitis is a worldwide health problem and significant cause of mortality. However, the disease etiology is largely unknown, which accounts for ineffective treatment and uncontrolled disease progression. In this study, we demonstrated the functional importance of the IL-17C/IL-17RE axis in Con A-induced hepatitis. Elevated IL-17C expression was detected in liver samples of both human and mouse autoimmune hepatitis. IL-17C, produced by hepatocytes, and its specific receptor IL-17RE on liver-resident T cells were both found to be required in Con A-induced liver damage. Mechanistically, IL-17C augmented the expression of IL-2 by intrahepatic CD4+ T cells to promote NK cell activation and liver damage. To our knowledge, our findings thus for the first time defined the indispensable role of IL-17C/IL-17RE in autoimmune hepatitis; this axis may serve as a novel drug target for the treatment of this disease.
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http://dx.doi.org/10.4049/jimmunol.1600977DOI Listing
January 2017

Piwil2 is reactivated by HPV oncoproteins and initiates cell reprogramming via epigenetic regulation during cervical cancer tumorigenesis.

Oncotarget 2016 Oct;7(40):64575-64588

Department of Obstetrics and Gynecology, China-Japan Friendship Hospital, Beijing, China.

The human papillomavirus (HPV) oncoproteins E6 and E7 are risk factors that are primarily responsible for the initiation and progression of cervical cancer, and they play a key role in immortalization and transformation by reprogramming differentiating host epithelial cells. It is unclear how cervical epithelial cells transform into tumor-initiating cells (TICs). Here, we observed that the germ stem cell protein Piwil2 is expressed in pre-cancerous and malignant lesions of the cervix and cervical cancer cell lines with the exception of the non-HPV-infected C33a cell line. Knockdown of Piwil2 by shRNA led to a marked reduction in proliferation and colony formation, in vivo tumorigenicity, chemo-resistance, and the proportion of cancer stem-like cells. In contrast, Piwil2 overexpression induced malignant transformation of HaCaT cells and the acquisition of tumor-initiating capabilities. Gene-set enrichment analysis revealed embryonic stem cell (ESC) identity, malignant biological behavior, and specifically, activation targets of the cell reprogramming factors c-Myc, Klf4, Nanog, Oct4, and Sox2 in Piwil2-overexpressing HaCaT cells. We further confirmed that E6 and E7 reactivated Piwil2 and that E6 and E7 overexpression resulted in a similar gene-set enrichment pattern as Piwil2 overexpression in HaCaT cells. Moreover, Piwil2 overexpression or E6 and E7 activation induced H3K9 acetylation but reduced H3K9 trimethylation, which contributed to the epigenetic reprogramming and ESC signature maintenance, as predicted previously. Our study demonstrates that Piwil2, reactivated by the HPV oncoproteins E6 and E7, plays an essential role in the transformation of cervical epithelial cells to TICs via epigenetics-based cell reprogramming.
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http://dx.doi.org/10.18632/oncotarget.11810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5323100PMC
October 2016

NK cell development requires Tsc1-dependent negative regulation of IL-15-triggered mTORC1 activation.

Nat Commun 2016 09 7;7:12730. Epub 2016 Sep 7.

Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100086, China.

Activation of metabolic signalling by IL-15 is required for natural killer (NK) cell development. Here we show that Tsc1, a repressor of mTOR, is dispensable for the terminal maturation, survival and function of NK cells but is critical to restrict exhaustive proliferation of immature NK cells and activation downstream of IL-15 during NK cell development. Tsc1 is expressed in immature NK cells and is upregulated by IL-15. Haematopoietic-specific deletion of Tsc1 causes a marked decrease in the number of NK cells and compromises rejection of 'missing-self' haematopoietic tumours and allogeneic bone marrow. The residual Tsc1-null NK cells display activated, pro-apoptotic phenotype and elevated mTORC1 activity. Deletion of Raptor, a component of mTORC1, largely reverses these defects. Tsc1-deficient NK cells express increased levels of T-bet and downregulate Eomes and CD122, a subunit of IL-15 receptor. These results reveal a role for Tsc1-dependent inhibition of mTORC1 activation during immature NK cell development.
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http://dx.doi.org/10.1038/ncomms12730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023956PMC
September 2016

The Self-Specific Activation Receptor SLAM Family Is Critical for NK Cell Education.

Immunity 2016 08 9;45(2):292-304. Epub 2016 Aug 9.

Institute for Immunology, School of Medicine and Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address:

NK cell education, a term describing a process for NK cell acquisition of functional competence, is primarily achieved by self-MHC-I-specific inhibitory receptors. In this study, we have demonstrated that SLAM family receptors (SFRs) redundantly expressed on hematopoietic cells function as self-specific activation receptors critical for NK cell education. To overcome gene redundancy, we generated mice simultaneously lacking seven SFRs, revealing that NK-cell-mediated rejection of semi-allogeneic hematopoietic cells largely depended on the presence of SFRs on target cells. This stimulatory effect was determined by the presence of SFR-coupled adaptors; however, SFR-deficient mice displayed enhanced reactivity to hematopoietic cells. These findings demonstrate that SFRs endow NK cells with an ability to kill hematopoietic cells during the effector phase; however, the sustained engagement of SFRs can desensitize NK cell responses during an education process. Therefore, self-specific activating ligands may be "tolerogens" for NK cells, akin to self-antigens that induce T cell tolerance.
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http://dx.doi.org/10.1016/j.immuni.2016.07.013DOI Listing
August 2016

A hematopoietic cell-driven mechanism involving SLAMF6 receptor, SAP adaptors and SHP-1 phosphatase regulates NK cell education.

Nat Immunol 2016 Apr 15;17(4):387-96. Epub 2016 Feb 15.

Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, Québec, Canada.

Activation of natural killer (NK) cells by hematopoietic target cells is controlled by the SLAM family of receptors and by the associated SAP family of adaptors. Here we found that SLAM receptors also enhanced NK cell activation by nonhematopoietic target cells, which lack ligands for SLAM receptors. This function was mediated by SLAMF6, a homotypic SLAM receptor found on NK cells and other hematopoietic cells, and was regulated by SAP adaptors, which uncoupled SLAM receptors from phosphatase SHP-1 and diminished the effect of SLAMF6 on NK cell responsiveness toward nonhematopoietic cells. Thus, in addition to their role in NK cell activation by hematopoietic cells, the SLAM-SAP pathways influence responsiveness toward nonhematopoietic targets by a process akin to NK cell 'education'.
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http://dx.doi.org/10.1038/ni.3369DOI Listing
April 2016

PDK1 orchestrates early NK cell development through induction of E4BP4 expression and maintenance of IL-15 responsiveness.

J Exp Med 2015 Feb 26;212(2):253-65. Epub 2015 Jan 26.

School of Medicine, and Center of Animal Facility, Tsinghua University, Beijing 100086, China

E4BP4, a circadian protein, is indispensable for NK cell development. It remains largely unknown which signal is required to induce E4BP4 expression and what effects it has during NK cell differentiation. Here, we reveal that PDK1, a kinase upstream of mTOR, connects IL-15 signaling to E4BP4. Early deletion of PDK1 caused a severe loss of NK cells and compromised antitumor activity in vivo. PDK1-deficient NK cells displayed much weaker IL-15-induced mTOR activation and E4BP4 induction, as well as remarkable reduction in CD122, a receptor subunit specifying NK cell responsiveness to IL-15. The phenotypes were partially reversible by ectopic expression of E4BP4 or bypassed activation of mTOR. We also determined that PDK1-mediated metabolic signaling was dispensable for NK cell terminal maturation and survival. Thus, we identify a role for PDK1 signaling as a key mediator in regulating E4BP4 expression during early NK cell development. Our findings underscore the importance of IL-15 self-responsiveness through a positive feedback loop that involves PDK1-mTOR-E4BP4-CD122 signaling.
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http://dx.doi.org/10.1084/jem.20141703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322053PMC
February 2015

SAP-regulated T Cell-APC adhesion and ligation-dependent and -independent Ly108-CD3ζ interactions.

J Immunol 2014 Oct 12;193(8):3860-71. Epub 2014 Sep 12.

Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China;

The germinal center response requires cooperation between Ag-specific T and B lymphocytes, which takes the form of long-lasting cell-cell conjugation in vivo. Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) is required for stable cognate T-B cell conjugation, whereas SLAM family transmembrane (TM) receptor Ly108 may negatively regulate this process. We show that, other than phosphotyrosine-binding, SAP does not harbor motifs that recruit additional signaling intermediates to stabilize T-B adhesion. Ly108 dampens T cell adhesion to not only Ag-presenting B cells, but also dendritic cells by inhibiting CD3ζ phosphorylation through two levels of regulated Ly108-CD3ζ interactions. Constitutively associated with Src homology 2 domain-containing tyrosine phosphatase-1 even in SAP-competent cells, Ly108 is codistributed with the CD3 complex within a length scale of 100-200 nm on quiescent cells and can reduce CD3ζ phosphorylation in the absence of overt TCR stimulation or Ly108 ligation. When Ly108 is engaged in trans during cell-cell interactions, Ly108-CD3ζ interactions are promoted in a manner that uniquely depends on Ly108 TM domain, leading to more efficient CD3ζ dephosphorylation. Whereas replacement of the Ly108 TM domain still allows the constitutive, colocalization-dependent inhibition of CD3ζ phosphorylation, it abrogates the ligation-dependent Ly108-CD3ζ interactions and CD3ζ dephosphorylation, and it abolishes the suppression on Ag-triggered T-B adhesion. These results offer new insights into how SAP and Ly108 antagonistically modulate the strength of proximal TCR signaling and thereby control cognate T cell-APC interactions.
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http://dx.doi.org/10.4049/jimmunol.1401660DOI Listing
October 2014

From the guest editors: Cancer-associated inflammation and tumor microenvironment.

Cancer J 2013 Nov-Dec;19(6):459-60

From the School of Medicine, Tsinghua University, Beijing, China.

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http://dx.doi.org/10.1097/PPO.0000000000000008DOI Listing
September 2014