scholarly journals Rosette-forming ability of thymus-derived lymphocytes in cell-mediated immunity. I. Delayed hypersensitivity and in vitro cytotoxicity.

1975 ◽  
Vol 141 (3) ◽  
pp. 584-599 ◽  
Author(s):  
B E Elliott ◽  
J S Haskill ◽  
M A Axelrad
Keyword(s):  
T Cell ◽  
In Vitro Cytotoxicity ◽  
Delayed Hypersensitivity ◽  
Velocity Sedimentation ◽  
Target Cells ◽  
Cell Mediated Immunity ◽  
Small Lymphocyte ◽  
Effector Cells ◽  
Effector T Cell

Effector cells in delayed hypersensitivity and in vitro cytotoxicity were studied in lymph node cells from animals immunized with sheep erythrocytes (SRBC) in complete Freund's adjuvant. Delayed hypersensitivity response (DHR) was assayed by the increase in foot pad swelling after the intrafoot pad injection of immune cells plus antigen. Cell-mediated cytotoxicity against SRBC was assayed by a microcytotoxicity test with sheep fibroblasts as target cells. Effector cells were antigen specific, sensitive to anti-theta serum plus complement (C), and insensitive to anti-Ig serum plus C. A nonrosette-forming (non-RFC) small lymphocyte effector T cell and a rosette-forming medium lymphocyte effector T cell were isolated by velocity sedimentation. The small lymphocyte non-RFC required a longer time than the medium lymphocyte RFC effector cell to produce maximum activity. Buoyant density failed to distinguish medium lymphocyte effector cells in DHR and in vitro cytotoxicity.

scholarly journals Cell-mediated lympholysis to H-2-matched target cells modified with a series of nitrophenyl compounds.

1976 ◽  
Vol 144 (4) ◽  
pp. 1134-1140 ◽  
Author(s):  
T G Rehn ◽  
J K Inman ◽  
G M Shearer
Keyword(s):  
T Cell ◽  
Target Cells ◽  
Cell Recognition ◽  
Receptor Model ◽  
Spleen Cells ◽  
Effector Cells ◽  
T Cell Recognition ◽  
Cytotoxic Effector

The specificity of C57BL/10 cytotoxic effector cells generated by in vitro sensitization with autologous spleen cells modified with a series of related nitrophenyl compounds was investigated. The failure of trinitrophenyl (TNP)-sensitized effector cells to lyse TNP-beta-alanylglycylglycyl(AGG)-modified target cells is presented as evidence contradicting the intimacy or dual receptor model or T-cell recognition in its simplest form. Data are also shown indicating that sensitization with N-(3-nitro-4-hydroxy-5-iodophenylacetyl)-AGG-modified stimulating cells generates noncross-reacting clones of cytotoxic effector cells.

scholarly journals Migration ofAntigen-Specific T Cells Away from CXCR4-Binding Human ImmunodeficiencyVirus Type 1gp120

2004 ◽  
Vol 78 (10) ◽  
pp. 5184-5193 ◽  
Author(s):  
Diana M. Brainard ◽  
William G. Tharp ◽  
Elva Granado ◽  
Nicholas Miller ◽  
Alicja K. Trocha ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cell ◽  
Active Movement ◽  
Target Cells ◽  
Cell Mediated Immunity ◽  
Cell Trafficking ◽  
Hiv 1

ABSTRACT Cell-mediated immunity depends in part on appropriate migration and localization of cytotoxic T lymphocytes (CTL), a process regulated by chemokines and adhesion molecules. Many viruses, including human immunodeficiency virus type 1 (HIV-1), encode chemotactically active proteins, suggesting that dysregulation of immune cell trafficking may be a strategy for immune evasion. HIV-1 gp120, a retroviral envelope protein, has been shown to act as a T-cell chemoattractant via binding to the chemokine receptor and HIV-1 coreceptor CXCR4. We have previously shown that T cells move away from the chemokine stromal cell-derived factor 1 (SDF-1) in a concentration-dependent and CXCR4 receptor-mediated manner. Here, we demonstrate that CXCR4-binding HIV-1 X4 gp120 causes the movement of T cells, including HIV-specific CTL, away from high concentrations of the viral protein. This migratory response is CD4 independent and inhibited by anti-CXCR4 antibodies and pertussis toxin. Additionally, the expression of X4 gp120 by target cells reduces CTL efficacy in an in vitro system designed to account for the effect of cell migration on the ability of CTL to kill their target cells. Recombinant X4 gp120 also significantly reduced antigen-specific T-cell infiltration at a site of antigen challenge in vivo. The repellant activity of HIV-1 gp120 on immune cells in vitro and in vivo was shown to be dependent on the V2 and V3 loops of HIV-1 gp120. These data suggest that the active movement of T cells away from CXCR4-binding HIV-1 gp120, which we previously termed fugetaxis, may provide a novel mechanism by which HIV-1 evades challenge by immune effector cells in vivo.

scholarly journals SEPARABLE POPULATIONS OF ACTIVATED THYMUS-DERIVED LYMPHOCYTES IDENTIFIED IN TWO ASSAYS FOR CELL-MEDIATED IMMUNITY TO MURINE TUMOR ALLOGRAFTS

1974 ◽  
Vol 140 (1) ◽  
pp. 267-289 ◽  
Author(s):  
Robert E. Tigelaar ◽  
R. M. Gorczynski
Keyword(s):  
Cytotoxic Activity ◽  
Velocity Sedimentation ◽  
Target Cells ◽  
Cell Mediated Immunity ◽  
Macrophage Migration ◽  
Inhibition Activity ◽  
Migration Inhibition ◽  
Spleen Cells ◽  
Macrophage Migration Inhibition

The immune response of C57BL mice to a DBA/2 tumor allograft has been assessed in two assays of cell-mediated immunity, the in vitro lysis of 51Cr-labeled target cells and the antigen-mediated inhibition of macrophage migration. Both assays were shown to be measuring a T-cell-mediated reaction. Three types of experiments suggested that distinct subpopulations of T cells mediate these reactions. The tissue distributions of these activities was distinctive; both activities were present in spleens from i.p. immunized mice, but only macrophage migration inhibition activity was found in the peripheral lymph nodes (PLN) of such mice. Adoptive transfer of immune spleen cells into irradiated syngeneic recipients revealed that while a substantial amount of migration inhibition activity could subsequently be found in PLN, cytotoxic activity was found predominantly in the spleens of these adoptive hosts. Velocity sedimentation analysis of immune cells 14 days after i.p. immunization indicated that while the majority of cytotoxic activity was associated with small and medium lymphocytes, the majority of migration inhibition activity was associated with medium and large lymphocytes. In addition, normal spleen cells were fractionated by velocity sedimentation immediately before allosensitization in vitro. Subsequent analysis of the sensitized fractions revealed that the activity profiles for cytotoxicity and macrophage migration inhibition were not coincident. The implications of these observations are discussed.

scholarly journals Specificity of cytotoxicity T cells directed to influenza virus hemagglutinin.

1979 ◽  
Vol 149 (4) ◽  
pp. 856-869 ◽  
Author(s):  
T J Braciale
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytotoxic T Cells ◽  
Type A ◽  
Cross Reactivity ◽  
Cytotoxic T Cell ◽  
Target Cells ◽  
Effector Cells ◽  
Cell Induction

Purified type A influenza viral hemagglutinin stimulates an in vitro cell-mediated cytotoxic cell response that exhibits a high degree of specificity for the immunizing hemagglutinin. The response magnitude is proportional to the hemagglutinin dose used for stimulation. The lytic activity of the effector cells is H-2 restricted. Analysis of the specificity of the response indicated that these cytotoxic T cells readily distinguish target cells expressing serologically unrelated hemagglutinin from target cells bearing hemagglutinins serologically related to the stimulating hemagglutinin. Further analysis of the fine specificity of cytotoxic T-cell recognition with serologically cross-reactive type A influenza hemagglutinins revealed a hierarchy of cross-reactivity among these hemagglutinins that was the converse of the serologic hierarchy. These results are discussed in terms of possible differences and similarities in the specificity repertoire of cytotoxic T cells and antibodies. Possible implications of these findings from the standpoint of cytotoxic T-cell induction are also discussed.

scholarly journals In Vitro and In Vivo Characterization of CD19/CD3 Tandab AFM11 and CD19/CD16A Tandab AFM12 Targeting NHL

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2763-2763
Author(s):  
Xing Zhao ◽  
Narendiran Rajasekaran ◽  
Uwe Reusch ◽  
Michael Weichel ◽  
Kristina Ellwanger ◽  
...  
Keyword(s):  
T Cell ◽  
Target Cell ◽  
Binding Sites ◽  
Effector Cell ◽  
Nk Cell ◽  
Target Cells ◽  
Tumor Target ◽  
Effector Cells

Abstract Introduction: CD19 is expressed by B cells from early development through differentiation into plasma cells, and represents a validated target for the development of therapeutic antibodies to treat B cell malignancies such as Non Hodgkin Lymphoma (NHL) and acute lymphoblastic leukemia (ALL). Different CD19-targeting T-cell engagers are investigated in clinical studies for the treatment of NHL or ALL, including Affimed's AFM11, a bispecific CD19/CD3 TandAb antibody, which is currently investigated in a phase 1 dose escalation study. Indeed, Affimed's bispecific tetravalent platform comprises not only T-cell engaging TandAbs with two binding sites for CD3, but also NK-cell recruiting TandAbs with two binding sites for CD16A. In the present study, Affimed's AFM11, was characterized and compared in in vitro and in vivo studies with the CD19/CD16A TandAb AFM12. Methods: Analogous to the CD19/CD3 TandAb AFM11, a bispecific tetravalent TandAb AFM12 was constructed with two binding sites for CD19 and two sites for CD16A. Both TandAbs were characterized side by side for their biophysical properties, binding affinities to CD19+ tumor target cells and to their respective effector cells by flow cytometry. Kinetics and dose-response characteristics were evaluated in in vitro cytotoxicity assays. Potency and efficacy of both TandAbs were compared on different CD19+ tumor target cell lines using primary human effector cells. To compare the efficacy of AFM11 and AFM12 a patient-derived tumor xenograft model was developed. Results: AFM12 mediated efficacious target cell lysis with a very fast on-set in vitro. Lysis induced by AFM11 was less efficacious (lower specific lysis than AFM12) but reproducibly more potent (lower EC50 value). In addition to the potency and efficacy of AFM11 and AFM12, different aspects of safety, such as effector cell activation in the presence and absence of target cells were investigated and will be described. Conclusions: Affimed's CD19/CD3 and CD19/CD16A TandAbs with identical anti-CD19 tumor-targeting domains but different effector cell-recruiting domains represent interesting molecules to study T-cell- or NK-cell-based immunotherapeutic approaches. The comparison of AFM11 and AFM12 demonstrated that AFM12-mediated lysis was fast and efficacious, whereas AFM11 showed a higher potency. In summary, the NK-cell recruiting TandAb AFM12 represents an alternative to T-cell recruiting molecules, as it may offer a different side effect profile, comparable to that of AFM13, the first NK-cell TandAb clinically investigated. Disclosures No relevant conflicts of interest to declare.

scholarly journals Requirement for hexose, unrelated to energy provision, in T-cell-mediated cytolysis at the lethal hit stage.

1978 ◽  
Vol 147 (6) ◽  
pp. 1551-1567 ◽  
Author(s):  
I C MacLennan ◽  
P Golstein
Keyword(s):  
Tissue Culture ◽  
T Cell ◽  
Culture Media ◽  
Krebs Cycle ◽  
Co2 Production ◽  
Target Cells ◽  
Significant Activity ◽  
Spleen Cells ◽  
Effector Cells

The requirement for D-glucose in T-cell-mediated cytolysis was studied using mouse spleen cells sensitized against alloantigens in vitro. Glucose was required for cytolysis: (a) cytolysis proceeded in a simple buffered salt solution containing Ca++ and Mg++ (low phosphate-buffered saline, LPBS) in the presence but not in the absence of added glucose; (b) 2-deoxy-D-glucose blocked cytolysis. The block by this agent was overcome by excess glucose added as late as 40 min after the inhibitor. This block was not due to inhibition of NADP reduction, since 2-deoxy-D-glucose failed to interfere with the rate of CO2 production by the pentose cycle which we found to be of significant activity in sensitized spleen cells; (c) dialyzed fetal bovine serum (DFBS) in LPBS supported cytolysis in the absence of added glucose. However, 2-deoxy-D-glucose was also inhibitory under these conditions, suggesting that carbohydrate was required here as well. Further results supported the conclusion that DFBS was not acting as a direct source of the required carbohydrate. The relationship between cytolysis, glucose requirement, and provision of energy was studied. As little as 0.1 mM D-glucose in LPBS supported cytolysis. At this glucose concentration, there was no measurable accumulation of lactate in sensitized spleen cells, but Krebs cycle activity was detectable. In 3 mM glucose or above, the range covered by standard tissue culture media, anaerobic glycolysis became a major source of energy in sensitized spleen cells. Consequently, it appears that in standard tissue culture medium, effector cells can generate sufficient energy for cytolysis either by aerobic or anaerobic metabolism. However, the addition of an energy source alone in the absence of glucose was insufficient to support cytolysis in LPBS. Pyruvate in LPBS did not support cytolysis but was shown to be a good substrate for aerobic metabolism in sensitized spleen cells. Glycogenic amino acids and glycerol also failed to support cytolysis. The stage of cytolysis at which glucose is required was investigated. Glucose was necessary for the calcium-dependent lethal hit phase, but not for the cytochalasin A-blockable recognition stage, nor for 51Cr release from injured target cells. Models for the lethal hit process are discussed, which are compatible with the observed requirement for certain hexoses unrelated to their capacity to serve as sources of energy.

scholarly journals The in vitro generation and sustained culture of nude mouse cytolytic T-lymphocytes.

1979 ◽  
Vol 149 (6) ◽  
pp. 1460-1476 ◽  
Author(s):  
S Gillis ◽  
N A Union ◽  
P E Baker ◽  
K A Smith
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Nude Mouse ◽  
Nude Mice ◽  
Bone Marrow Cells ◽  
Target Cells ◽  
Cytolytic T Lymphocytes ◽  
Effector Cells ◽  
Major Function

In addition to allowing for the long-term culture of both murine and human cytolytic T lymphocytes, T-cell growth factor (TCGF) functions as the key proliferation-inducing second signal in both T-cell antigen sensitization and mitogenesis. The observation that thymocytes responded normally to T-cell mitogens in the presence of TCGF, prompted the investigation of the effect of TCGF on nude mouse lymphocyte responses in vitro. We found that spleen, lymph node, and bone marrow cells, isolated from nude mice, were incapable of producing TCGF yet responded normally to T-cell mitogen sensitization provided stimulation was conducted in the presence of TCGF. Nude mouse spleen cells were also capable of responding to alloantigen sensitization in mixed lymphocyte cultures (NLMC) conducted in the presence of TCGF. Thy-1 antigen-positive cells harvested from TCGF-supplemented nude mouse MLC effectively mediated the cytolysis of alloantigen-specific target cells as tested in standard 51Cr-release assays. Cytolytic nude mouse effector cells have remained in TCGF-dependent culture for over 3 mo during which they have continued to mediate significant levels of alloantigen-specific cytolytic reactivity. These results suggest that prothymocytes present in nude mice are capable of responding to immunologic stimuli by differentiating, in vitro, into cytolytic T lymphocytes and that furthermore, a major function of the thymus may be to effect the maturation of TCGF-producing cells.

scholarly journals The induction of cell-mediated immunity and tolerance with protein antigens coupled to syngeneic lymphoid cells.

1979 ◽  
Vol 149 (3) ◽  
pp. 758-773 ◽  
Author(s):  
S D Miller ◽  
R P Wetzig ◽  
H N Claman
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Lymphoid Cells ◽  
Delayed Hypersensitivity ◽  
Cell Mediated Immunity ◽  
Protein Antigens ◽  
Cyt C

A mouse model of cell-mediated immunity (CMI) and tolerance to protein antigens horse gamma globulin (HoGG) and cytochrome (Cyt C) was investigated. A reliable CMI response as measured in vivo by ear swelling or by an in vitro T-cell proliferation assay could be induced by one of two methods: (a) sensitization by antigen-complete Freund's adjuvant in the base of the tail, or (b) sensitization by s.c. injection of antigen coupled to syngeneic lymphoid cells. The in vivo response exhibited characteristic CMI parameters, delayed kinetics, and transfer by viable T cells. Prior i.v. injection of HoGG-modified lymphoid cells (HoGG-LC) or Cyt C-LC before sensitization resulted in a rapidly induced, dose-dependent, antigen-specific suppression of both in vivo and in vitro manifestations of the CMI response. In addition, tolerance in this system was transferrable by an antigen-specific suppressor T cell (Ts). The Ts were found to diminish the in vivo ear swelling reaction in recipient animals, but had no effect on the in vitro T-cell proliferative response of the recipients. In contrast to the rapid development of tolerance in donor mice (phenotypic tolerance), transferrable Ts were first demonstrable 4--7 d posttolerization. This latter result indicates that at least two mechanisms of tolerance are operative in this system: the rapid induction of clone inhibition of reactive T cells and the slower induction of Ts. These results indicate again that the mode of antigen presentation is crucial in determining the immunologic outcome. In these experiments, cell-bound proteins injected subcutaneously led to delayed hypersensitivity while the same antigens injected intravenously led to tolerance. These results are considered in the light of recent experiments which show that T cells recognize antigens on cells in association with major histocompatibility complex products. We believe the following pathways are involved. In sensitization via subcutaneous injection of HoGG-LC, antigen reaches the lymph node via lymphatic pathways which lead to immunogenic macrophage-associated presentation and the activation of delayed hypersensitivity T cells (TDH). In tolerization via intravenous injection of HoGG-LC, antigen (a) reaches the lymph node via the blood, probably directly meeting the TDH, preventing its subsequent activation by immunogenic HoGG (clone inhibition) and (b) reaches the spleen, also via the blood, activating suppressor T cells.

Transfer of Human T-Cell Receptors (TCR) Containing Murine Chimeric Constant Beta-Gamma-Chain Sequences Reduces the Risk of Mixed Heterodimers and Shows Enhanced in Vitro-Accumulation of TCR-Tranduced Effector Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3583-3583
Author(s):  
Angela Krackhardt ◽  
Xiaoling Liang ◽  
Ingrid G Schuster ◽  
Luise U Weigand ◽  
Elfriede Eppinger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Therapeutic Approach ◽  
Cell Clone ◽  
Target Cells ◽  
Malignant Diseases ◽  
Effector Cells ◽  
T Cell Clone

Abstract Abstract 3583 Poster Board III-520 Introduction Adoptive transfer of T-cell receptor (TCR)-transduced T cells may represent an attractive and promising novel approach to specifically treat malignant diseases and has been previously successfully applied in the clinic. This approach promises the availability of sufficient numbers of effector cells with defined specificity for any tumor-associated antigen as also TCR from T cells with specificity for tumor-associated self antigens usually deleted in the autologous host may be isolated from an allorestricted or xenorestricted environment. We have previously identified the HLA-A2-allorestricted T-cell clone (SK22) with specificity for a peptide derived from Formin-like protein 1 (FMNL1) restrictedly expressed in hematopoietic tissue and overexpressed in diverse leukemias and other malignant tissue. SK22 demonstrated specific cytotoxicity against FMNL1-overexpressing cells as EBV-transformed B cells, lymphoma cell lines and native malignant cells derived from patients with chronic lymphocytic leukemia whereas healthy tissue was mainly spared. The TCR of this T cell clone may therefore represent a suitable tool for the treatment of diverse malignant diseases using TCR-transduced T cells. However, there are different concerns which need to be addressed to further improve this therapeutic approach. First, the formation of heterodimers between endogenous TCR chains and transduced TCR chains derived from receptors with low interchain affinity may abrogate specific TCR function and harbours a particular risk for unknown specificities. Although a number of TCR chain modifications has been previously applied to solve this problem further improvements are necessary. Second, longterm survival of TCR-transduced T cells has been demonstrated to be critical for the effectivity of this approach and novel approaches are needed. Methods and Results We have isolated the TCR-chain genes of the FMNL1-specific T cell clone SK22 and cloned them into the retroviral vector pMP71. Transduction of unmodified TCR-chain genes of SK22 in CD8α-transfected TCR-deficient Jurkat76 cells resulted in multimer-positive cells indicating that correct TCR-chain genes have been isolated. However, peripheral blood mononuclear cells (PBMC) transduced with these native TCR chains did neither show TCR expression nor specific T-cell function suggesting that TCR SK22 represents a weak TCR with low interchain affinity. Expression and function of this TCR could be significantly improved by current optimization strategies as codon-optimization and murinization of constant chains. Effector cells transduced with these optimized TCR chain genes showed reactivity against transformed cells of different origin whereas non-transformed HLA-A2 positive target cells as lung fibroblasts, embryonic cardiomyocytes, CD4- and CD8-positive T cells as well as activated PBMC were not recognized. However, substantial mispairing persisted despite of murinization of constant chain sequences. Using human TCR chain genes containing murinized chimeric constant βγ-chains previously reported to exert improved signaling in murine T cells and cell lines, we created a hybrid TCR with high functional efficiency after transfer in human effector cells. Moreover, usage of murinized chimeric constant βγ-chains of SK22 clearly reduced the formation of heterodimers in human PBMC. In addition, we observed enhanced in vitro-accumulation of CD8- and CD4-positive cells expressing the transgenic receptor when optimized murinized chimeric constant βγ-chains in comparison to optimized murinized constant β-chains without γ-chain sequences were used. These results could be confirmed after transfer of two alternative TCR with specificities for HER2/neu and GP100 containing murinized chimeric constant βγ-chains. Conclusion These data show that transfer of the optimized TCR SK22 may be an attractive therapeutic tool for the treatment of malignancies of hematologic and other origin. Moreover, the transfer of TCR chain genes containing optimized murinized chimeric constant βγ-chains may have a significant impact on the improvement of safety and efficiency of this therapeutic approach. Disclosures: No relevant conflicts of interest to declare.

Evidence for Associations Between Th1/Th17 “Hybrid” Phenotype and Altered Lipometabolism in Very Severe Graves Orbitopathy

2020 ◽  
Vol 105 (6) ◽  
pp. 1851-1867 ◽  
Author(s):  
Sijie Fang ◽  
Shuo Zhang ◽  
Yazhuo Huang ◽  
Yu Wu ◽  
Yi Lu ◽  
...  
Keyword(s):  
T Cell ◽  
Th17 Cell ◽  
Th17 Cells ◽  
T Cell Subsets ◽  
Th1 Cell ◽  
Effector T Cell ◽  
Cell Lineages ◽  
Graves Orbitopathy ◽  
Ifn Γ

Abstract Purpose The purpose of this article is to investigate the characteristics of Th1-cell and Th17-cell lineages for very severe Graves orbitopathy (GO) development. Methods Flow cytometry was performed with blood samples from GO and Graves disease (GD) patients and healthy controls, to explore effector T-cell phenotypes. Lipidomics was conducted with serum from very severe GO patients before and after glucocorticoid (GC) therapy. Immunohistochemistry and Western blotting were used to examine orbital-infiltrating Th17 cells or in vitro models of Th17 polarization. Results In GD, Th1 cells predominated in peripheral effector T-cell subsets, whereas in GO, Th17-cell lineage predominated. In moderate-to-severe GO, Th17.1 cells expressed retinoic acid receptor-related orphan receptor-γt (RORγt) independently and produced interleukin-17A (IL-17A), whereas in very severe GO, Th17.1 cells co-expressed RORγt and Tbet and produced interferon-γ (IFN-γ). Increased IFN-γ–producing Th17.1 cells positively correlated with GO activity and were associated with the development of very severe GO. Additionally, GC therapy inhibited both Th1-cell and Th17-cell lineages and modulated a lipid panel consisting of 79 serum metabolites. However, in GC-resistant, very severe GO, IFN-γ–producing Th17.1 cells remained at a high level, correlating with increased serum triglycerides. Further, retro-orbital tissues from GC-resistant, very severe GO were shown to be infiltrated by CXCR3+ Th17 cells expressing Tbet and STAT4 and rich in triglycerides that promoted Th1 phenotype in Th17 cells in vitro. Conclusions Our findings address the importance of Th17.1 cells in GO pathogenesis, possibly promoting our understanding of the association between Th17-cell plasticity and disease severity of GO.

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