scholarly journals Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion

2010 ◽  
Vol 207 (3) ◽  
pp. 505-520 ◽  
Author(s):  
Xiaoyuan Huang ◽  
Xiangyang Bai ◽  
Yang Cao ◽  
Jingyi Wu ◽  
Mei Huang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
B Cell Lymphoma ◽  
Global Gene Expression ◽  
T Cell Response ◽  
Th1 Polarization

Angiogenesis is increasingly recognized as an important prognosticator associated with the progression of lymphoma and as an attractive target for novel modalities. We report a previously unrecognized mechanism by which lymphoma endothelium facilitates the growth and dissemination of lymphoma by interacting with circulated T cells and suppresses the activation of CD4+ T cells. Global gene expression profiles of microdissected endothelium from lymphoma and reactive lymph nodes revealed that T cell immunoglobulin and mucin domain–containing molecule 3 (Tim-3) was preferentially expressed in lymphoma-derived endothelial cells (ECs). Clinically, the level of Tim-3 in B cell lymphoma endothelium was closely correlated to both dissemination and poor prognosis. In vitro, Tim-3+ ECs modulated T cell response to lymphoma surrogate antigens by suppressing activation of CD4+ T lymphocytes through the activation of the interleukin-6–STAT3 pathway, inhibiting Th1 polarization, and providing protective immunity. In a lymphoma mouse model, Tim-3–expressing ECs promoted the onset, growth, and dissemination of lymphoma by inhibiting activation of CD4+ T cells and Th1 polarization. Our findings strongly argue that the lymphoma endothelium is not only a vessel system but also a functional barrier facilitating the establishment of lymphoma immune tolerance. These findings highlight a novel molecular mechanism that is a potential target for enhancing the efficacy of tumor immunotherapy and controlling metastatic diseases.

Global Gene Expression Profiles of Activated CD4+CD25high (Regulatory) and CD4+CD25− (Non-Regulatory) T Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3308-3308
Author(s):  
ChaoYan Liu ◽  
Qi-Hong Sun ◽  
Gian Paolo Visentin
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Cd4 T Cells ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Global Gene Expression ◽  
Differentially Expressed ◽  
Platelet Factor ◽  
Homogeneous Population

Abstract Autoreactive T and B cells can be detected in healthy individuals but are normally kept in check by regulatory mechanisms. Among those is an active suppression of naïve T cells by endogenous T regulatory (Tr) cells. Several types of Tr cells exist, including CD4+ T cells which constitutively express the IL-2 receptor α chain (CD25), do not secrete IL-10, and suppress immune responses via direct cell-to-cell interactions. CD4+CD25+ T regulatory cells represent 5%–10% of the endogenous CD4+ T cells subset and are able to suppress CD4+ and CD8+ T cell responses in vitro and in vivo upon TCR ligation. Our recent observation that human platelet factor 4 (PF4; CXCL4) inhibits the proliferative response of human CD4+CD25− T cells, while inducing expansion of CD4+CD25+ Tr cells, and that PF4-induced CD4+CD25+ Tr cells lose their potent suppressor function in vitro, suggests a previously unrecognized role of PF4 in the regulation of immune responsiveness (Liu, et al. J Immunol174:2680–86, 2005). A large body of evidence suggests that human CD4+CD25+ Tr cells share many of the characteristics of murine CD4+CD25+ Tr cells. McHugh et al. (Immunity16:311–23, 2002), have successfully used the microarray approach to identify genes differentially expressed in resting CD4+CD25+ and CD4+CD25− mouse T cells, but with the only exception of a small preliminary report (Pati et al. Ann N Y Acad Sci. 1005:279–83, 2003), little information is available on the gene expression profile of human CD4+CD25+ and CD4+CD25− T cells. We performed global gene expression analysis using oligo-DNA microarrays (CodeLink, Amersham Biosciences) that monitor the expression of whole human genome, to define the gene expression profiles in CD4+CD25+ Tr cells stimulated by anti-CD3 mAb and exposed to PF4. CD4+ T cells were isolated from normal donor’s peripheral blood mononuclear cells by positive selection on magnetic beads (Miltenyi Biotec, Auburn, CA), then labeled with PE-conjugated anti-CD4 and FITC-conjugated anti-CD25 and sorted on a FACStar (BD Biosciences, San Jose, CA) to obtain a homogeneous population of T cells consisting of CD4+CD25+ Tr cells expressing CD25 at high levels (CD4+CD25high) and CD4+CD25− T cells (non-regulatory). Total RNA was extracted from the freshly isolated CD4+CD25high and CD4+CD25− T cells subsets, stimulated with anti-CD3 mAb in the presence or the absence of PF4 for 24 hours. Using this approach, we have identified a little over 100 genes that are differentially expressed, in the presence of PF4, in CD4+CD25+ Tr cells following activation with anti-CD3 mAb. We have focused our attention on about 40 target genes whose increased expression has been validated using real time PCR and, were appropriate, at the protein levels, by flow cytometry or Luminex 100 multiplex cytokine quantification (Table 1). Our data suggest that PF4 modulates proliferation and function of CD4+CD25+ Tr cells by the coordinate increasing expression of a relatively large number of genes, coupled with a further enhanced expression of a limited number of growth promoting genes and the specific silencing of a small subset of negative growth regulatory genes.

Functional T Cell Array Reveals Pre-Treatment Expanded Terminal Effector Memory Response Is Associated with Lenalidomide Failure in Non-Del(5q) Myelodysplastic Syndrome.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1759-1759
Author(s):  
P.K. Epling-Burnette ◽  
JianXiang Zou ◽  
Jeffrey S. Painter ◽  
Dung-Tsa Chen ◽  
Jimmy Fulp ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Myelodysplastic Syndrome ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Erythroid Differentiation ◽  
T Cell Response ◽  
Effector Memory ◽  
Terminal Effector

Abstract Abstract 1759 Poster Board I-785 Lenalidomide (LEN) is a thalidomide derivative with proven efficacy for the treatment of patients with myelodysplastic syndrome (MDS). High rates of erythroid and cytogenetic response in patients with chromosome 5q deletion [del(5q)] produced the first FDA-approved karyotype-specific treatment for this disease. Transfusion-independence rates of approximately 25% have been reported previously for patients with non-[del(5q)] and efficacy in this population has been linked to the promotion of erythroid differentiation. Because impaired erythroid differentiation in lower-risk MDS may occur through several pathophysiological mechanisms, the identification of additional factors with predictive value for both response and failure to LEN are needed to optimize success of treatment. In addition to affecting erythroid differentiation, LEN has well-known potential for immune modulation and generates highly potent effector T cell responses in vitro and in vivo by potentiating T cell receptor signaling. Immune deregulation mediated by autoreactive effector T cells has been linked to impaired erythropoiesis and granulopoiesis in a distinct subset of MDS patients raising the question of whether LEN impacts the disease process in this subset of patients. To understand the relationship between T cell deregulation and LEN response, we conducted a pilot study of 13 low/INT-1-risk non-del (5q) MDS patients (7 responders and 6 non-responders) treated with LEN and determined 23 covariates related to functional T cell response measured prior to treatment and then correlated to treatment outcome. Of these 23 covariates, multiple T cell immune parameters were analyzed but were not associated with response including interferon-g (IFNg) production by CD4+ T cells (p=0.9) and CD8+ T cells (p=0.27), Tumor Necrosis Factor (TNF)-a production by CD4+ T cells (p=1.0) and CD8+ T cells (p=0.8), TCR-associated proliferation within the CD4+ (p=1.0) and CD8+ (p=0.4) compartment, CD4/CD8 ratio (p=0.3), percentage of CD4+ (p=0.5) and CD8+ (p=0.5) T lymphocytes, and the percentage of naïve and three different types of memory CD4+ T cells. Analysis was performed using two-group comparison statistical tests (two-sample t-test and Wilcoxon rank sum test) to compare responders (R) vs non-responders (NR). Only one factor was independently linked to LEN response. Results showed that a higher percentage of CD8 T cells (mean 56% in NR vs 32% in R) with a Terminal Effector Memory [TEM]) phenotype (CD45RA+/CD62L-) was associated with LEN failure (p=0.02). This population of T cells occurs at a low frequency in healthy individuals but can be induced to differentiate in vitro under constant exposure to long-term antigen and cytokine stimulation. We have shown previously that CD8+ TEM T cells are expanded in patients with impaired myelopoiesis due to immune dysregulation in Large Granular Lymphocyte (LGL) leukemia. In conclusion, these results suggest that CD8+ terminal effector memory expansion may be linked to immune deregulation in MDS and represents an important biomarker with negative predictive importance for LEN response in non-del(5q) low-risk MDS. Disclosures No relevant conflicts of interest to declare.

Enhancing Cytotoxicity of Autologous T Cells in AML By Blockade of CTLA-4 and PD-1

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4057-4057 ◽  
Author(s):  
Kirsten Marie Boughan ◽  
Xiaohua Chen ◽  
Paul Szabolcs
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Response ◽  
Conflicts Of Interest ◽  
Expression Profiles ◽  
T Cell Response ◽  
Inhibitory Receptors

Abstract Background: AML remains a disease diagnosed in the aging population with chemotherapy followed by bone marrow transplant in some cases being the standard of care. Although response rates remain around 50-60%, treatment related mortality and disease relapse remain high. Adoptive immunotherapy, especially those targeting T cell co-inhibitory receptors, has proven successful in solid malignancies however, AML remains less explored. Our laboratory has previously demonstrated the feasibility to generate autologous AML reactive T cells in vitro (Mehta/Szabolcs; Immunotherapy 2016). It was noted that "resistant" AML blasts over expressed a number of genes associated with immunosuppressive characteristics. Over expression of these genes may induce T cell functional exhaustion. Therefore, we hypothesized that blocking PD-1 and/or CTLA-4 during co-culture with IFNg activated AML blasts, may enhance T cell activation and cytotoxicity. To test this hypothesis, we tested CTL responses against AML blasts and IFNg ELISpot formation after blocking with PD-1, CTLA-4 or both receptors, and compared the response in untreated T cells. Gene expression profiles of co-stimulatory/co-inhibitory receptors were also monitored to test for correlation. Methods: We evaluated 12 patients with newly diagnosed AML under an IRB approved protocol with written informed consent of patients. Mononuclear cell preparation was generated from fresh marrow samples or drawn from a biorepository of previously cryopreserved leukophereses. T cells were then purified using immunomagnetic CD3/CD28 beads (Life technologies) and cultivated in media with IL-2 and IL-7 for 2 weeks. AML blasts were cultured over a supporting layer of mesenchymal stromal cells (MSCs) derived from healthy BM donors for 1 week and then cryopreserved. T cells were then co-cultured with restored and irradiated autologous AML cells at an effector: target (E: T) ratio of 5:1 to 40:1. AML and T cells were co-cultured in the presence of Ipilimumab (anti-CTLA-4), or Nivolumab (anti-PD-1), or a combination of both drugs. T cells and AML were re stimulated in X-vivo 15 with IL-12, IL-15 and IL-2 weekly x 3weeks. T cell response to AML was quantitated by IFNg ELISpot assay and Europium TDA (EuTDA) CTL assays independently. Co-stimulatory/co-inhibitory expression on T cells was examined with RT-q PCR assay. Paired-sample student t test was used for statistical analysis with p<0.05. Results and Discussion: Out of 12 samples, 10 (83%) yielded viable AML cells available for cytotoxicity assay. One third (33%) of co-cultures exhibited a positive T cell response in CTL assays ("killers"). There was no difference in CTL activity by blockade of either PD-1 or CTL-4 (Fig 1). IFN-ɣ spot formation in ELISpot was observed in 4/10 samples (40%) with statistical significance noted in cells blocked with PD-1 as compared to all other blockade types (Fig 2). The results indicated that in vitro priming with autologous AML blasts or together with blocking PD-1 can enhance T cell response in 33-40%. By gene expression analysis, the ratio of co-stimulatory to co-inhibitory genes was calculated. In PD-1 blocked cells, the ratio of activation/inhibition was not impacted in T cells from "killers" (0.9; p=0.1), however, T cells from "non-killer cells" had a diminished ratio due to higher expression of co-inhibitory molecules (0.4; p=0.04) (Fig 3). This trend was also present in CTLA-4 blocked cells (0.85; p=0.4 in killers vs 0.54; p=0.03 in non-killers) (data not shown). Interestingly, dual blockage failed to influence gene expression ratio, data not shown. Conclusion: The above studies demonstrate that cytotoxicity can be achieved in T cells when primed against autologous AML. PD-1 blockade can enhance IFNg production and cytotoxic responses, but CTLA-4 and dual blockade failed to enhance T cell function. The upregulation of an inhibitory pattern of genes in T cells that did not express cytotoxicity (non-killers) could allude to an "inhibitory phenotype" that may be resistant to immunotherapy drug blockade and requires further study. Disclosures No relevant conflicts of interest to declare.

scholarly journals 2081

2017 ◽  
Vol 1 (S1) ◽  
pp. 55-56
Author(s):  
Farha Sherani ◽  
Duane Moogk ◽  
Anuj Bapodra ◽  
Karolina Malecek ◽  
Una Moran ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Expression Profiles ◽  
Cytokine Expression ◽  
T Cell Response ◽  
Tumor Rejection ◽  
Cytokine Profiles ◽  
Ifn Γ

OBJECTIVES/SPECIFIC AIMS: To characterize the CD4+ T-cell response during CTLA-4 blockade immunotherapy with ipilimumab in patients with metastatic melanoma by correlating cytokine profiles with phenotypic changes in the intratumoral lymphocyte compartment of tumor biopsies obtained before and after treatment. METHODS/STUDY POPULATION: Peripheral blood mononuclear cell samples were obtained from patients with metastatic melanoma undergoing monotherapy with ipilimumab via the Interdisciplinary Melanoma Cooperative Group at New York University Langone Medical Center. We isolated CD4+ T-cells and used a cytometric bead array assay following in vitro activation with anti-CD3, anti-CD28 antibodies to characterize cytokine expression profiles by quantifying IFN gamma, IL-2, IL-4, IL-6, IL-10, IL-17, and TNF-α at 5 time points during therapy. In total, 53 peripheral blood samples were included from 12 patients. To correlate cytokine profiles with CD4+ T-cell phenotypes in the intratumoral lymphocyte compartment, multiplex immunofluorescence was performed using CD4, CD8, CCR7, CD45RO, and FOXP3 antibodies on tumors before and after treatment with ipilimumab. RESULTS/ANTICIPATED RESULTS: Patients with evidence of clinical benefit (CB), as defined by having achieved partial response or stable disease, were compared with nonresponders (NR). All patients had an increase in IFN-γ, IL-2, and IL-10 secretion by CD4+ T-cells during ipilimumab therapy. NR had a statistically higher increase in all 3 cytokines. Mean IL-10 secretion was 22.3-fold higher compared with patients with CB (p value 0.0458; 95% CI=0.6676–43.89). Mean IFN-γ secretion was 12.4-fold higher from baseline levels in NR compared with CB (p value 0.046; 95% CI=0.3589–24.35). Mean IL-2 secretion was 6.9-fold higher in NR compared with CB (p value 0.032; 95% CI=0.9688–12.75). There were no statistically significant differences seen in the secretion of IL-4, IL-6, IL-17, or TNF-α. Multiplex immunofluorescence for immune profiling of 20 pre and post treatment tumor biopsies is ongoing. We expect to see distinct intratumoral lymphocyte compartment changes which correlate with clinical response and the above described differential cytokine profiles. Specifically, we anticipate CB patients will have increased intratumoral effector T-cells and decreased regulatory T-cells when compared with their NR counterparts. DISCUSSION/SIGNIFICANCE OF IMPACT: Cytokine expression profiles of peripheral blood CD4+ T-cells have not been previously correlated with patient response in patients undergoing treatment with ipilimumab. We describe distinct secretion profiles for IFN-γ, IL-2, and IL-10 for CB Versus NR patients. NR had a statistically higher increase in IL-10, an inhibitory cytokine which typically indicates upregulation of regulatory T-cells and consequent immune escape. Increased secretion of IL-2 and IFN-γ suggests skewing towards a Th1 type, anti-tumor effector T-cell response; these cytokines increased with ipilimumab treatment in both patient groups. However, the mean increase was several fold higher in NR. Recent evidence suggests loss of the interferon gamma pathway in tumor cells confers resistance to anti-CTLA4 therapy. Chronic IFN-γ secretion is associated with an exhausted T-cell phenotype and impaired tumor rejection. Therefore, higher increases in IFN-γ secretion by CD4+ T-cells in NR suggest impaired IFN-γ dependent tumor rejection in these patients. Our findings suggest IFN-γ, IL-2, and IL-10 cytokine expression profiles can be useful as biomarkers for response to ipilimumab treatment.

scholarly journals THU0046 A PIPELINE TO STUDY ANTIGEN-SPECIFIC CD4+ T CELLS IN RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 235.1-236
Author(s):  
R. Kumar ◽  
N. Yoosuf ◽  
C. Gerstner ◽  
S. Turcinov ◽  
K. Chemin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Tenascin C ◽  
Tetramer Staining ◽  
Tcr Repertoire ◽  
Citrullinated Antigen

Background:Autoimmunity to citrullinated autoantigens forms a critical component of disease pathogenesis in rheumatoid arthritis (RA). Presence of anti-citrullinated protein antibodies (ACPAs) in patients has high diagnostic value. Recently, several citrullinated antigen specific CD4+T cells have been described. However, detailed studies of their T-cell receptor usage and in-vivo profile suffer from the disadvantage that these cells are present at very low frequencies. In this context, we here present a pipeline for TCR repertoire analysis of antigen-specific CD4+T cells from RA patients, including both citrulline and influenza (control) specificities using in-vitro peptide challenge induced-cell expansion.Objectives:To enable studies of the T cell repertoire of citrullinated antigen-specific CD4+T cells in rheumatoid arthritisMethods:Peripheral blood mononuclear cells (PBMCs) (n=7) and synovial fluid mononuclear cells (SFMCs) (n=5) from HLA-DR*0401-postive RA patients were cultured in the presence of citrullinated Tenascin C peptide cocktails or influenza peptides (positive control). Citrulline reactive cells were further supplemented with recombinant human IL-15 and IL-7 on day 2. All cultures were replenished with fresh medium on day 6 and rIL-2 was added every 2 days from then. Assessment of proportion of peptide-HLA-tetramer positive cells was performed using flow cytometry whereby individual antigen-specific CD4+T cells were sorted into 96-well plates containing cell lysis buffer, followed by PCR-based alpha/beta TCR sequencing. TCR sequencing data was demultiplexed and aligned for TCR gene usage using MiXCR. Some tetramer positive cells were sorted into complete medium containing human IL-2 and PHA for expansion of antigen-specific cells. Cells were supplemented with irradiated allogenic PBMCs (30 times number of antigen specific cells). Clones of antigen specific CD4+T cells were further subjected to tetramer staining to confirm expansion of cells.Results:As evidenced by increase in frequency of tetramer positive CD4+T cells, in vitro peptide stimulation resulted in expansion of both influenza specific (Fig. 1a) and citrullinated antigen specific (Fig. 1b) CD4+T cells. Polyclonal in-vitro expansion of tenascin C tetramer positive sorted cells followed by tetramer staining further confirmed antigen specificity and enrichment for antigen specific CD4+T cells after polyclonal stimulation (Fig.1c). TCR repertoire analysis in PB and SF dataset from the first patient showed clonal expansion of influenza specific cells in both sites. Synovial fluid had more diversity of expanding clones as compared to paired PB, with few expanded clones being shared among SF and PB. We observed a more diverse TCR repertoire in citrulline specific CD4+T cells. We also observed sharing of TCR alpha chains among different citrulline specific CD4+T cell clones.Fig. 1In-vitroexpansion of antigen specific CD4+T cells:Conclusion:This method provides a highly suitable approach for investigating TCR specificities of antigen specific CD4+T cells under conditions of low cell yields. Building on this dataset will allow us to assess specific features of TCR usage of autoreactive T cells in RA.PBMCs were cultured in presence of (a) influenza (HA, MP54) and (b) citrullinated tenascin peptides. The proportion of antigen specific CD4+T cells was assessed using HLA-class II tetramer staining. We observed an increase in frequency of (a) Infleunza specific cells (red dots in upper left and lower right quadrants) and (b) citrullinated tenascin C specific cells (red dots in lower right quadrant), at day 13 post culture as compared to day 3. (c) Sorting of citrullinated tenascin specific CD4+T cells, followed by PHA expansion resulted in visible increase in proportion of citrullinated tenascin specific CD4+T cells.Disclosure of Interests:Ravi kumar: None declared, Niyaz Yoosuf: None declared, Christina Gerstner: None declared, Sara Turcinov: None declared, Karine Chemin: None declared, Vivianne Malmström Grant/research support from: VM has had research grants from Janssen Pharmaceutica

scholarly journals Cd40-Independent Pathways of T Cell Help for Priming of Cd8+ Cytotoxic T Lymphocytes

2000 ◽  
Vol 191 (3) ◽  
pp. 541-550 ◽  
Author(s):  
Zhengbin Lu ◽  
Lingxian Yuan ◽  
Xianzheng Zhou ◽  
Eduardo Sotomayor ◽  
Hyam I. Levitsky ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Cell Communication ◽  
Cd8 T Cell ◽  
Cd4 Help ◽  
T Cell Help

In many cases, induction of CD8+ CTL responses requires CD4+ T cell help. Recently, it has been shown that a dominant pathway of CD4+ help is via antigen-presenting cell (APC) activation through engagement of CD40 by CD40 ligand on CD4+ T cells. To further study this three cell interaction, we established an in vitro system using dendritic cells (DCs) as APCs and influenza hemagglutinin (HA) class I and II peptide–specific T cell antigen receptor transgenic T cells as cytotoxic T lymphocyte precursors and CD4+ T helper cells, respectively. We found that CD4+ T cells can provide potent help for DCs to activate CD8+ T cells when antigen is provided in the form of either cell lysate, recombinant protein, or synthetic peptides. Surprisingly, this help is completely independent of CD40. Moreover, CD40-independent CD4+ help can be documented in vivo. Finally, we show that CD40-independent T cell help is delivered through both sensitization of DCs and direct CD4+–CD8+ T cell communication via lymphokines. Therefore, we conclude that CD4+ help comprises at least three components: CD40-dependent DC sensitization, CD40-independent DC sensitization, and direct lymphokine-dependent CD4+–CD8+ T cell communication.

MOG extracellular domain (p1–125) triggers elevated frequency of CXCR3+ CD4+ Th1 cells in the CNS of mice and induces greater incidence of severe EAE

2014 ◽  
Vol 20 (10) ◽  
pp. 1312-1321 ◽  
Author(s):  
Jyothi T Mony ◽  
Reza Khorooshi ◽  
Trevor Owens
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Cd4 T Cells ◽  
Cd8 T Cell ◽  
Interferon Γ ◽  
T Cell Response ◽  
Receptor Expression ◽  
Myelin Proteins ◽  
Mhc Ii

Background: Myelin-specific T cells are implicated in multiple sclerosis (MS) and drive experimental autoimmune encephalomyelitis (EAE). EAE is commonly induced with short peptides, whereas in MS, whole myelin proteins are available for immune response. We asked whether immunization with the immunoglobulin-like domain of myelin oligodendrocyte glycoprotein (MOGIgd, residues 1–125) might induce distinct CD4+ T-cell response and/or a stronger CD8+ T-cell response, compared to the 21 amino acid immunodominant MHC II-associating peptide (p35–55). Objectives: Compare both EAE and T-cell responses in C57BL/6 mice immunized with MOGIgd and MOG p35–55. Methods: Cytokine production, and chemokine receptor expression by CD4+ and CD8+ T cells in the mouse central nervous system (CNS), were analyzed by flow cytometry. Results: MOGIgd triggered progression to more severe EAE than MOG p35–55, despite similar time of onset and overall incidence. EAE in MOGIgd-immunized mice was characterized by an increased percentage of CXCR3+ interferon-γ-producing CD4+ T cells in CNS. The CD8+ T-cell response to both immunogens was similar. Conclusions: Increased incidence of severe disease following MOGIgd immunization, accompanied by an increased percentage of CD4+ T cells in the CNS expressing CXCR3 and producing interferon-γ, identifies a pathogenic role for interferon-γ that is not seen when disease is induced with a single Major Histocompatibility Complex (MHC) II-associating epitope.

scholarly journals CD4+ T Cells from Glutamic Acid Decarboxylase (GAD)65-specific T Cell Receptor Transgenic Mice Are Not Diabetogenic and Can Delay Diabetes Transfer

2002 ◽  
Vol 196 (4) ◽  
pp. 481-492 ◽  
Author(s):  
Kristin V. Tarbell ◽  
Mark Lee ◽  
Erik Ranheim ◽  
Cheng Chi Chao ◽  
Maija Sanna ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
T Cell Receptor ◽  
Glutamic Acid Decarboxylase ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Acid Decarboxylase ◽  
Gad 65

Glutamic acid decarboxylase (GAD)65 is an early and important antigen in both human diabetes mellitus and the nonobese diabetic (NOD) mouse. However, the exact role of GAD65-specific T cells in diabetes pathogenesis is unclear. T cell responses to GAD65 occur early in diabetes pathogenesis, yet only one GAD65-specific T cell clone of many identified can transfer diabetes. We have generated transgenic mice on the NOD background expressing a T cell receptor (TCR)-specific for peptide epitope 286–300 (p286) of GAD65. These mice have GAD65-specific CD4+ T cells, as shown by staining with an I-Ag7(p286) tetramer reagent. Lymphocytes from these TCR transgenic mice proliferate and make interferon γ, interleukin (IL)-2, tumor necrosis factor (TNF)-α, and IL-10 when stimulated in vitro with GAD65 peptide 286–300, yet these TCR transgenic animals do not spontaneously develop diabetes, and insulitis is virtually undetectable. Furthermore, in vitro activated CD4 T cells from GAD 286 TCR transgenic mice express higher levels of CTL-associated antigen (CTLA)-4 than nontransgenic littermates. CD4+ T cells, or p286-tetramer+CD4+ Tcells, from GAD65 286–300-specific TCR transgenic mice delay diabetes induced in NOD.scid mice by diabetic NOD spleen cells. This data suggests that GAD65 peptide 286–300-specific T cells have disease protective capacity and are not pathogenic.

The lymphoid chemokine CCL21 costimulates naïve T cell expansion and Th1 polarization of non-regulatory CD4+ T cells

2004 ◽  
Vol 231 (1-2) ◽  
pp. 75-84 ◽  
Author(s):  
Kenneth Flanagan ◽  
Dorota Moroziewicz ◽  
Heesun Kwak ◽  
Heidi Hörig ◽  
Howard L. Kaufman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cell Expansion ◽  
T Cell Expansion ◽  
Th1 Polarization ◽  
Naïve T Cell ◽  
Naive T Cell
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