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Enhanced Induction of T Cell Immunity Using Dendritic Cells Pulsed with HIV Tat and HCMV-pp65 Fusion Protein In Vitro.

Jung Sun PARK ; Soo Young PARK ; Hyun Il CHO ; Hyun Jung SOHN ; Tai Gyu KIM

Immune Network.2011;11(3):182-189. doi:10.4110/in.2011.11.3.182

BACKGROUND: Cytotoxic T lymphocytes (CTLs) appear to play an important role in the control and prevention of human cytomegalovirus (HCMV) infection. The pp65 antigen is a structural protein, which has been defined as a potential target for effective immunity against HCMV infection. Incorporation of an 11 amino acid region of the HIV TAT protein transduction domain (Tat) into protein facilitates rapid, efficient entry into cells. METHODS: To establish a strategy for the generation of HCMV-specific CTLs in vitro, recombinant truncated N- and C-terminal pp65 protein (pp65 N&C) and N- and C-terminal pp65 protein fused with Tat (Tat/pp65 N&C) was produced in E.coli system. Peripheral blood mononuclear cells were stimulated with dendritic cells (DCs) pulsed with pp65 N&C or Tat/pp65 N&C protein and immune responses induced was examined using IFN-gamma ELISPOT assay, cytotoxicity assay and tetramer staining. RESULTS: DCs pulsed with Tat/pp65N&C protein could induce higher T-cell responses in vitro compared with pp65N&C. Moreover, the DCs pulsed with Tat/pp65 N&C could stimulate both of CD8+ and CD4+ T-cell responses. The T cells induced by DCs pulsed with Tat/pp65 N&C showed higher cytotoxicity than that of pp65-pulsed DCs against autologous lymphoblastoid B-cell line (LCL) expressing the HCMV-pp65 antigen. CONCLUSION: Our results suggest that DCs pulsed with Tat/pp65 N&C protein effectively induced pp65-specific CTL in vitro. Tat fusion recombinant protein may be useful for the development of adoptive T-cell immunotherapy and DC-based vaccines.
B-Lymphocytes ; Cytomegalovirus ; Dendritic Cells ; Enzyme-Linked Immunospot Assay ; HIV ; Humans ; Immunotherapy ; T-Lymphocytes ; T-Lymphocytes, Cytotoxic ; tat Gene Products, Human Immunodeficiency Virus ; Vaccines

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Identification of CM1 as a Pathogenic Factor in Inflammatory Diseases and Cancer.

Seyeon BAE ; Hyemin KIM ; Yeon Sil YU ; Na Eun LEE ; Joo Myoung KONG ; Hang Rae KIM ; Young Il HWANG ; Yeong Wook SONG ; Jae Seung KANG ; Wang Jae LEE

Immune Network.2011;11(3):175-181. doi:10.4110/in.2011.11.3.175

BACKGROUND: CM1 (centrocyte/-blast marker 1) was defined by a mAb against concanavalin A (Con A) activated PBMC. It is expressed in germinal center of human tonsil and on the surface of activated PBMC as well as cancer cells. Recently, increased productions of pro-inflammatory mediators were detected from activated PBMC by CM1 ligation. METHODS: However, there is a limitation to explain the exact role of CM1 on inflammation and its related mechanisms, since the identity of CM1 is still not clarified. In our previous study, we have already confirmed that soluble form of CM1 was produced by Raji. Therefore, we performed Q-TOF analysis after immunoprecipitation of concentrated Raji culture supernatant using anti-CM1 mAbs. RESULTS: As a result, we found that CM1 is identical to enolase-1(ENO1), a glycolytic enzyme, and we confirmed that results by silencing ENO1 using siRNA. It was also confirmed through competition assay between anti-CM1 and anti-ENO1 mAbs. Finally, we investigated the possible role of CM1 in inflammatory response and cancer. The ligation of CM1 on Raji cells with anti-CM1 mAbs induces the extensive production of prostaglandin E2(PGE2). In addition, the increased activity of matrix metalloproteinase (MMP)-2/9 was shown in NCI-N87, stomach cancer cell line by CM1 stimulation. CONCLUSION: CM1 is identical to ENO1 and it might be an important role in the regulation of inflammatory responses.
Cell Line ; Concanavalin A ; Dinoprostone ; Germinal Center ; Humans ; Immunoprecipitation ; Inflammation ; Ligation ; Palatine Tonsil ; RNA, Small Interfering ; Stomach Neoplasms

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Enhancement of Allergen-induced Airway Inflammation by NOX2 Deficiency.

Hee Yeon WON ; Eun Jung JANG ; Hyun Jung MIN ; Eun Sook HWANG

Immune Network.2011;11(3):169-174. doi:10.4110/in.2011.11.3.169

BACKGROUND: NADPH oxidase (NOX) modulates cell proliferation, differentiation and immune response through generation of reactive oxygen species. Particularly, NOX2 is recently reported to be important for regulating Treg cell differentiation of CD4+ T cells. METHODS: We employed ovalbumin-induced airway inflammation in wild-type and NOX2-deficient mice and analyzed tissue histopathology and cytokine profiles. RESULTS: We investigated whether NOX2-deficiency affects T cell-mediated airway inflammation. Ovalbumin injection which activates T cell-mediated allergic response increased airway inflammation in wild-type mice, as evidenced by increased immune cell infiltration, allergic cytokine expression, and goblet cell hyperplasia in the lung. Interestingly, NOX2 knockout (KO) mice were more susceptible to allergen-induced lung inflammation compared to wild-type mice. Immune cells including neutrophils, lymphocytes, macrophages, and eosinophils were drastically infiltrated into the lung of NOX2 KO mice and mucus secretion was substantially increased in deficiency of NOX2. Furthermore, inflammatory allergic cytokines and eotaxin were significantly elevated in NOX2 KO mice, in accordance with enhanced generation of inflammatory cytokines interleukin-17 and interferon-gamma by CD4+ T cells. CONCLUSION: These results indicate that NOX2 deficiency favorably produces inflammatory cytokines by T cells and thus increases the susceptibility to severe airway inflammation.
Animals ; Cell Proliferation ; Cytokines ; Eosinophils ; Goblet Cells ; Hyperplasia ; Inflammation ; Interferon-gamma ; Interleukin-17 ; Lung ; Lymphocytes ; Macrophages ; Mice ; Mucus ; NADPH Oxidase ; Neutrophils ; Ovalbumin ; Pneumonia ; Reactive Oxygen Species ; T-Lymphocytes ; T-Lymphocytes, Regulatory

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Formulation and Characterization of Antigen-loaded PLGA Nanoparticles for Efficient Cross-priming of the Antigen.

Young Ran LEE ; Young Hee LEE ; Sun A IM ; Kyungjae KIM ; Chong Kil LEE

Immune Network.2011;11(3):163-168. doi:10.4110/in.2011.11.3.163

BACKGROUND: Nanoparticles (NPs) prepared from biodegradable polymers, such as poly (D,L-lactic acid-co-glycolic acid) (PLGA), have been studied as vehicles for the delivery of antigens to phagocytes. This paper describes the preparation of antigen-loaded PLGA-NPs for efficient cross-priming. METHODS: NPs containing a similar amount of ovalbumin (OVA) but different sizes were produced using a micromixer-based W/O/W solvent evaporation procedure, and the efficiency of the NPs to induce the cross-presentation of OVA peptides were examined in dendritic cells (DCs). Cellular uptake and biodistribution studies were performed using fluorescein isothiocyanate (FITC)-loaded NPs in mice. RESULTS: The NPs in the range of 1.1~1.4microm in size were the most and almost equally efficient in inducing the cross-presentation of OVA peptides via H-2Kb molecules. Cellular uptake and biodistribution studies showed that opsonization of the NPs with mouse IgG greatly increased the percentage of FITC-positive cells in the spleen and lymph nodes. The major cell type of FITC-positive cells in the spleen was macrophages, whereas that of lymph nodes was DCs. CONCLUSION: These results show that IgG-opsonized PLGA-NPs with a mean size of 1.1microm would be the choice of biodegradable carriers for the targeted-delivery of protein antigens for cross-priming in vivo.
Animals ; Cross-Priming ; Dendritic Cells ; Fluorescein ; Immunoglobulin G ; Isothiocyanates ; Lactic Acid ; Lymph Nodes ; Macrophages ; Mice ; Nanoparticles ; Ovalbumin ; Ovum ; Peptides ; Phagocytes ; Polyglycolic Acid ; Polymers ; Spleen

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Ribosomal Protein L19 and L22 Modulate TLR3 Signaling.

Eun Jeong YANG ; Jin Won SEO ; In Hong CHOI

Immune Network.2011;11(3):155-162. doi:10.4110/in.2011.11.3.155

BACKGROUND: Toll-like receptor 3 (TLR3) recognizes double-stranded RNA (dsRNA) and induces inflammation. In this study we attempted to ascertain if there are endogenous host molecules controlling the production of cytokines and chemokines. Two candidates, ribosomal protein L19 and L22, were analyzed to determine if they influence cytokine production followed by TLR3 activation. In this study we report that L19 acts upon production of IP-10 or IL-8 differently in glioblastoma cells. METHODS: L19 or L22 was transfected into HEK293-TLR3, A549 or A172 cells. After treatment with several inhibitors of NF-kB, PI3K, p38 or ERK, production of IL-8 or IP-10 was measured by ELISA. siRNA was introduced to suppress expression of L19. After Vesicular stomatitis virus infection, viral multiplication was measured by western blot. RESULTS: L19 increased ERK activation to produce IL-8. In A172 cells, in which TLR3 is expressed at endosomes, L19 inhibited interferon regulatory factor 3 (IRF3) activation and IP-10 production to facilitate viral multiplication, whereas L19 inhibited viral multiplication in A549 cells bearing TLR3 on their cell membrane. CONCLUSION: Our results suggest that L19 regulates TLR3 signaling, which is cell type specific and may be involved in pathogenesis of autoimmune diseases and chronic inflammatory diseases.
Autoimmune Diseases ; Chemokines ; Cytokines ; Endosomes ; Enzyme-Linked Immunosorbent Assay ; Glioblastoma ; Inflammation ; Interferon Regulatory Factor-3 ; Interleukin-8 ; NF-kappa B ; Ribosomal Proteins ; RNA, Double-Stranded ; RNA, Small Interfering ; Toll-Like Receptor 3 ; Ursidae ; Vesicular Stomatitis ; Viruses

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Engagement of CD99 Reduces AP-1 Activity by Inducing BATF in the Human Multiple Myeloma Cell Line RPMI8226.

Minchan GIL ; Hyo Kyung PAK ; Seo Jeong PARK ; A Neum LEE ; Young Soo PARK ; Hyangsin LEE ; Hyunji LEE ; Kyung Eun KIM ; Kyung Jin LEE ; Dok Hyun YOON ; Yoo Sam CHUNG ; Chan Sik PARK

Immune Network.2015;15(5):260-267. doi:10.4110/in.2015.15.5.260

CD99 signaling is crucial to a diverse range of biological functions including survival and proliferation. CD99 engagement is reported to augment activator protein-1 (AP-1) activity through mitogen-activated protein (MAP) kinase pathways in a T-lymphoblastic lymphoma cell line Jurkat and in breast cancer cell lines. In this study, we report that CD99 differentially regulated AP-1 activity in the human myeloma cell line RPMI8226. CD99 was highly expressed and the CD99 engagement led to activation of the MAP kinases, but suppressed AP-1 activity by inducing the expression of basic leucine zipper transcription factor, ATF-like (BATF), a negative regulator of AP-1 in RPMI8226 cells. By contrast, engagement of CD99 enhanced AP-1 activity and did not change the BATF expression in Jurkat cells. CD99 engagement reduced the proliferation of RPMI8226 cells and expression of cyclin 1 and 3. Overall, these results suggest novel CD99 functions in RPMI8226 cells.
Breast Neoplasms ; Cell Line* ; Cyclins ; Humans* ; Jurkat Cells ; Leucine Zippers ; Lymphoma ; Multiple Myeloma* ; Phosphotransferases ; Transcription Factor AP-1* ; Transcription Factors

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Altered Gut Microbiota Composition in Rag1-deficient Mice Contributes to Modulating Homeostasis of Hematopoietic Stem and Progenitor Cells.

Ohseop KWON ; Seungwon LEE ; Ji Hae KIM ; Hyekang KIM ; Seung Woo LEE

Immune Network.2015;15(5):252-259. doi:10.4110/in.2015.15.5.252

Hematopoietic stem and progenitor cells (HSPCs) can produce all kind of blood lineage cells, and gut microbiota that consists of various species of microbe affects development and maturation of the host immune system including gut lymphoid cells and tissues. However, the effect of altered gut microbiota composition on homeostasis of HSPCs remains unclear. Here we show that compositional change of gut microbiota affects homeostasis of HSPCs using Rag1(-/-) mice which represent lymphopenic condition. The number and proportions of HSPCs in Rag1(-/-) mice are lower compared to those of wild types. However, the number and proportions of HSPCs in Rag1(-/-) mice are restored as the level of wild types through alteration of gut microbiota diversity via transferring feces from wild types. Gut microbiota composition of Rag1(-/-) mice treated with feces from wild types shows larger proportions of family Prevotellaceae and Helicobacterceae whereas lower proportions of family Lachnospiraceae compared to unmanipulated Rag1(-/-) mice. In conclusion, gut microbiota composition of lymphopenic Rag1(-/-) mice is different to that of wild type, which may lead to altered homeostasis of HSPCs.
Animals ; Feces ; Homeostasis* ; Humans ; Immune System ; Lymphocytes ; Mice* ; Microbiota* ; Stem Cells*

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Galectin-9 is Involved in Immunosuppression Mediated by Human Bone Marrow-derived Clonal Mesenchymal Stem Cells.

Si Na KIM ; Hyun Joo LEE ; Myung Shin JEON ; Tacghee YI ; Sun U SONG

Immune Network.2015;15(5):241-251. doi:10.4110/in.2015.15.5.241

Bone marrow-derived mesenchymal stem cells (MSCs) have immunomodulatory properties and can suppress exaggerated pro-inflammatory immune responses. Although the exact mechanisms remain unclear, a variety of soluble factors are known to contribute to MSC-mediated immunosuppression. However, functional redundancy in the immunosuppressive properties of MSCs indicates that other uncharacterized factors could be involved. Galectin-9, a member of the beta-galactoside binding galectin family, has emerged as an important regulator of innate and adaptive immunity. We examined whether galectin-9 contributes to MSC-mediated immunosuppression. Galectin-9 was strongly induced and secreted from human MSCs upon stimulation with pro-inflammatory cytokines. An in vitro immunosuppression assay using a knockdown approach revealed that galectin-9-deficient MSCs do not exert immunosuppressive activity. We also provided evidence that galectin-9 may contribute to MSC-mediated immunosuppression by binding to its receptor, TIM-3, expressed on activated lymphocytes, leading to apoptotic cell death of activated lymphocytes. Taken together, our findings demonstrate that galectin-9 is involved in MSC-mediated immunosuppression and represents a potential therapeutic factor for the treatment of inflammatory diseases.
Adaptive Immunity ; Apoptosis ; Cell Death ; Cytokines ; Galectins ; Humans* ; Immunosuppression* ; Lymphocytes ; Mesenchymal Stromal Cells*

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A New Triggering Receptor Expressed on Myeloid Cells (TREM) Family Member, TLT-6, is Involved in Activation and Proliferation of Macrophages.

Kyung Jong WON ; Sung Won PARK ; Seunghoon LEE ; Il Keun KONG ; Jung Il CHAE ; Bokyung KIM ; Eun Jong LEE ; Dong Ku KIM

Immune Network.2015;15(5):232-240. doi:10.4110/in.2015.15.5.232

The triggering receptor expressed on myeloid cells (TREM) family, which is abundantly expressed in myeloid lineage cells, plays a pivotal role in innate and adaptive immune response. In this study, we aimed to identify a novel receptor expressed on hematopoietic stem cells (HSCs) by using in silico bioinformatics and to characterize the identified receptor. We thus found the TREM-like transcript (TLT)-6, a new member of TREM family. TLT-6 has a single immunoglobulin domain in the extracellular region and a long cytoplasmic region containing 2 immunoreceptor tyrosine-based inhibitory motif-like domains. TLT-6 transcript was expressed in HSCs, monocytes and macrophages. TLT-6 protein was up-regulated on the surface of bone marrow-derived and peritoneal macrophages by lipopolysaccharide stimulation. TLT-6 exerted anti-proliferative effects in macrophages. Our results demonstrate that TLT-6 may regulate the activation and proliferation of macrophages.
Adaptive Immunity ; Computational Biology ; Computer Simulation ; Cytoplasm ; Hematopoietic Stem Cells ; Humans ; Immunoglobulins ; Macrophages* ; Macrophages, Peritoneal ; Monocytes ; Myeloid Cells*

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Selection of Thymocytes Expressing Transgenic TCR Specific for a Minor Histocompatibility Antigen, H60.

Ji Min JU ; Min Bum KIM ; Su Jeong RYU ; Joo Young KIM ; Jun CHANG ; Eun Young CHOI

Immune Network.2015;15(5):222-231. doi:10.4110/in.2015.15.5.222

Minor histocompatibility antigens are MHC-bound peptides and contribute to the generation of allo-responses after allogeneic transplantation. H60 is a dominant minor H antigen that induces a strong CD8 T-cell response in MHC-matched allogeneic transplantation settings. Here, we report establishment of a TCR transgenic mouse line named J15, wherein T cells express TCRs specific for H60 in complex with H-2K(b), and different fates of the thymocytes expressing J15 TCRs in various thymic antigenic environments. Thymocytes expressing the J15 TCRs were positively selected and differentiated into CD8+ single positive (SP) cells in the thymus of C57BL/6 mice, wherein the cognate antigen H60 is not expressed. However, thymocytes were negatively selected in thymus tissue where H60 was transgenically expressed under the control of the actin promoter, with double-positive stages of cells being deleted. Despite the ability of the H60H peptide (LTFHYRNL) variant to induce cytotoxic activity from H60-specific CTL lines at ~50% of the activity induced by normal H60 peptides (LTFNYRNL), J15-expressing thymocytes were positively selected in the thymus where the variant H60H was transgenically expressed. These results demonstrate that a single amino-acid change in the H60 epitope peptide influences the fate of thymocytes expressing the cognate TCR.
Actins ; Animals ; Histocompatibility Antigens* ; Histocompatibility* ; Mice ; Mice, Transgenic ; Minor Histocompatibility Antigens ; Peptides ; T-Lymphocytes ; Thymocytes* ; Thymus Gland ; Transplantation, Homologous

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