scholarly journals Interleukin 2 upregulates expression of its receptor on a T cell clone.

1985 ◽  
Vol 161 (6) ◽  
pp. 1575-1580 ◽  
Author(s):  
T R Malek ◽  
J D Ashwell
Keyword(s):  
T Cell ◽  
Cell Surface ◽  
Messenger Rna ◽  
Cell Clone ◽  
Interleukin 2 ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Initial Acquisition ◽  
T Cell Clone ◽  
Stimulation Of

Stimulation of a class II-restricted, antigen-specific T cell clone with interleukin 2 (IL-2) resulted in substantial increases in both cell surface IL-2 receptor (IL-2-R) and cytoplasmic IL-2-R messenger RNA (mRNA), whereas no increase was observed for cell-surface expression of Thy-1 and L3T4 antigens, and only a modest increase in Thy-1 mRNA was observed. These experiments demonstrate that, after initial acquisition of the IL-2-R, IL-2 as well as antigen is able to directly upregulate both the level of IL-2-R mRNA and cell surface IL-2-R molecules.

scholarly journals Clonotypic structures involved in antigen-specific human T cell function. Relationship to the T3 molecular complex.

1983 ◽  
Vol 157 (2) ◽  
pp. 705-719 ◽  
Author(s):  
S C Meuer ◽  
K A Fitzgerald ◽  
R E Hussey ◽  
J C Hodgdon ◽  
S F Schlossman ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
T Cell ◽  
Cell Surface ◽  
Cell Function ◽  
Cell Clone ◽  
Interleukin 2 ◽  
Cytotoxic T Cell ◽  
Surface Molecules ◽  
Human T Cell ◽  
T Cell Clone

Monoclonal antibodies were produced against a human cytotoxic T cell clone, CT8III (specificity: HLA-A3), with the view of defining clonally restricted (clonotypic) surface molecules involved in its antigen recognition function. Two individual antibodies, termed anti-Ti1A and anti-Ti1B, reacted exclusively with the CT8III clone when tested on a panel of 80 additional clones from the same donor, resting or activated T cells, B cells, macrophages, thymocytes, or other hematopoietic cells. More importantly, the two antibodies inhibited cell-mediated killing and antigen-specific proliferation of the CT8III clone but did not affect the functions of any other clone tested. This inhibition was not secondary to generalized abrogation of the CT8III clone's function, because interleukin 2 responsiveness was enhanced. To examine the relationship of the structures defined by anti-clonotypic antibodies with known T cell surface molecules, antibody-induced modulation studies and competitive binding assays were performed. The results indicated that the clonotypic structures were associated with, but distinct from, the 20,000-mol wt T3 molecule expressed on all mature T lymphocytes. Moreover, in contrast to anti-T3, anti-Ti1A and anti-Ti1B each immunoprecipitated two molecules of 49,000 and 43,000-mol wt from 131I-labeled CT8III cells under reducing conditions. The development of monoclonal antibodies to such polymorphic T cell surface structures should provide important probes to further define the surface receptor for antigen.

Physiological Non-Responsiveness and Absence of Activation Induced Cell Death of T Cells Rapidly Re-Expressing Retrovirally Introduced TCRs after T Cell Activation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2301-2301
Author(s):  
Marleen van Loenen ◽  
Renate Hagedoorn ◽  
Esther van Egmond ◽  
Roelof Willemze ◽  
J.H. Frederik Falkenburg ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Cell Surface ◽  
Refractory Period ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Functional Study ◽  
Kinetics Of ◽  
Stimulation Of

Abstract TCR transfer to engineer tumor specific T cells may be an alternative strategy for adoptive immunotherapy. We previously have shown that TCR-transduced T cells are capable of recognizing targets both via the endogenous and the introduced TCR. Stimulation of the TCR induces internalization of TCRs leading to a refractory period with a high activation threshold. Since the introduced TCR is regulated by a viral promotor which is constantly activated, we investigated whether modulation of the introduced TCRs after antigen specific triggering occurred in a physiological manner compared to the endogenous TCR. CMV specific T cells were retrovirally transduced with the hematopoietic minor histocompatibility antigen HA-2 specific TCR. TCR transduced T cells were antigen specifically triggered via either the introduced HA-2 (HA-2 TCR) or the endogenous CMV specific TCR (CMV TCR). At various time points after stimulation cell surface expression of the TCRαß-complexes and the BV-chain of the CMV TCR and HA-2 TCR was studied with monoclonal antibodies. Tetramers specific for the CMV TCR or HA-2 TCR were used to distinguish the TCRs from chimeric TCRαß-complexes. Stimulation via the CMV TCR or the HA-2 TCR resulted in similar internalization of approximately 50% of the TCRs. Preferentially, but not solely, the triggered TCRs were internalized. In contrast to the kinetics of internalization, the kinetics of TCR re-expression after stimulation differed considerably between the endogenous CMV and the introduced HA-2 TCR. The introduced HA-2 TCR was already re-expressed at the cell surface 24h after stimulation, while 70% of the endogenous CMV TCR still was internalized 72h after stimulation. This rapid synthesis of HA-2 TCRs could lead to enhanced competition for cell surface expression. Indeed, when TCR cell surface expression of the HA-2 TCR restored, cell surface expression of the CMV TCR decreased even further. When T cells were analyzed 4h after stimulation for cytolytic reactivity, both T cells stimulated via the HA-2 and the CMV TCR were non-responsive, correlating with low TCR expression. Although the HA-2 TCR was re-expressed at the cell surface 48h after stimulation, still no cytolytic activity via either the HA-2 or the CMV TCR was found. At this timepoint the level of expression of adhesion molecules and the amount of intracellular granzyme B after an initial decline was comparable to non-stimulated T cells. However, cell surface expression of the CD8 coreceptor was still diminished, resulting in low T cell avidity. To analyze whether stimulation via rapidly re-expressed HA-2 TCRs would lead to antigen induced cell death (AICD), T cells were stimulated via the HA-2 TCR after an initial stimulation and analyzed at different timepoints. In agreement with their non-responsiveness in the functional study, no increased AICD after specific stimulation via the HA-2 TCR was observed. In conclusion, we observed physiological internalization of TCRs which were regulated by a retroviral promotor after antigen specific triggering, but the introduced TCR was more rapidly re-expressed at the cell surface. Despite different TCR make up early after stimulation, in these T cells physiological non-responsiveness and no increased AICD was found after stimulation of the re-expressed introduced TCR, illustrating that cell mechanisms other than TCR cell surface expression like CD8 downregulation are also involved in providing a protective refractory period.

Significance of circulating T-cell clones in Sézary syndrome

Blood ◽  
2006 ◽  
Vol 107 (10) ◽  
pp. 4030-4038 ◽  
Author(s):  
Nicolas Ortonne ◽  
Delphine Huet ◽  
Caroline Gaudez ◽  
Anne Marie-Cardine ◽  
Valérie Schiavon ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Clone ◽  
Cell Receptor ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Malignant Cells ◽  
T Cell Clones ◽  
Cell Clones ◽  
T Cell Clone ◽  
T Cell Clonality

Identification of malignant Sézary cells by T-cell receptor (TCR) clonality studies is routinely used for the diagnosis of Sézary syndrome, but T-cell clones expressed in a single patient have never been accurately characterized. We previously reported that CD158k expression delineates Sézary syndrome malignant cells, and, more recently, we identified vimentin at the surface membranes of Sézary cells and normal activated lymphocytes. In the present study, T-cell clones from 13 patients with Sézary syndrome were identified by immunoscopy and further characterized in the blood according to their TCR Vβ, CD158k, and vimentin cell-surface expression. We found in most patients a unique malignant T-cell clone that coexpressed CD158k and vimentin and that, when patients were tested, was also present in the skin. However, in some patients we detected the presence of a nonmalignant circulating clone expressing high amounts of vimentin and lacking CD158k. These results indicate that clonal expansion may originate from circulating malignant and nonmalignant CD4+ T cell populations in patients with Sézary syndrome. Identification of the malignant cells in Sézary syndrome cannot be achieved by T-cell clonality studies or by TCR Vβ monoclonal antibody (mAb) analysis alone; it also relies on CD158k phenotyping.

scholarly journals T Cell Activity Correlates with Oligomeric Peptide-Major Histocompatibility Complex Binding on T Cell Surface

2001 ◽  
Vol 276 (50) ◽  
pp. 47320-47328 ◽  
Author(s):  
Jennifer Buslepp ◽  
Rui Zhao ◽  
Debora Donnini ◽  
Douglas Loftus ◽  
Mohamed Saad ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Cell Clone ◽  
Cell Activity ◽  
Class I ◽  
Antigenic Peptides ◽  
Major Histocompatibility ◽  
Class I Mhc ◽  
T Cell Clone

Recognition of virally infected cells by CD8+T cells requires differentiation between self and nonself peptide-class I major histocompatibility complexes (pMHC). Recognition of foreign pMHC by host T cells is a major factor in the rejection of transplanted organs from the same species (allotransplant) or different species (xenotransplant). AHIII12.2 is a murine T cell clone that recognizes the xenogeneic (human) class I MHC HLA-A2.1 molecule (A2) and the syngeneic murine class I MHC H-2 Dbmolecule (Db). Recognition of both A2 and Dbare peptide-dependent, and the sequences of the peptides recognized have been determined. Alterations in the antigenic peptides bound to A2 cause large changes in AHIII12.2 T cell responsiveness. Crystal structures of three representative peptides (agonist, null, and antagonist) bound to A2 partially explain the changes in AHIII12.2 responsiveness. Using class I pMHC octamers, a strong correlation is seen between T cell activity and the affinity of pMHC complexes for the T cell receptor. However, contrary to previous studies, we see similar half-lives for the pMHC multimers bound to the AHIII12.2 cell surface.

IgG plasma cells display a unique spectrum of leukocyte adhesion and homing molecules

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2905-2912 ◽  
Author(s):  
Gregory H. Underhill ◽  
Heather A. Minges-Wols ◽  
Jamie L. Fornek ◽  
Pamela L. Witte ◽  
Geoffrey S. Kansas
Keyword(s):  
B Cells ◽  
Cell Surface ◽  
Messenger Rna ◽  
Plasma Cells ◽  
Leukocyte Adhesion ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Leukocyte Function ◽  
Lymph Node Cells ◽  
Cell Adhesion Molecule 1

Abstract Long-lived antibody-secreting plasma cells are formed in the secondary lymphoid organs and subsequently home to the bone marrow, although the mechanisms that control this migration remain primarily unknown. In this study, we show that IgG plasma cells constitute a significant fraction of cervical lymph node cells from older mice deficient in both E- and P-selectin (E/P−/−), and that these cells can be prospectively isolated by phenotype. These IgG plasma cells were polyclonal, cytoplasmic Ig+, spontaneously secreted antibody, were in the G0/G1 phase of the cell cycle, and failed to express multiple B-cell surface markers. The plasma cells exhibited up-regulated cell surface expression of multiple adhesion molecules, including α4 and leukocyte function-associated antigen 1 (LFA-1) integrins, CD44, and P-selectin glycoprotein ligand 1 (PSGL-1). IgG plasma cells bound to vascular cell adhesion molecule 1 (VCAM-1) significantly better than IgM+B cells, indicating that the α4 integrins were constitutively active. A subset of IgG plasma cells also bound hyaluronic acid, the ligand for CD44. In addition, the IgG plasma cells interacted strongly with E-selectin, but poorly with P-selectin, despite elevated levels of PSGL-1 protein. The preferential interaction of plasma cells with E-selectin, but not P-selectin, correlated with elevated α1,3-fucosyltransferase-VII messenger RNA levels, but selective down-regulation of core 2 β1-6-N-glucosaminyltransferase levels, compared to B cells. These results demonstrate a unique adhesion profile for murine IgG plasma cells. Furthermore, the E/P−/− mice represent a novel system to isolate and purify significant numbers of primary IgG plasma cells.

scholarly journals A Next Generation Bivalent Human Ad5 COVID-19 Vaccine Delivering Both Spike and Nucleocapsid Antigens Elicits Th1 Dominant CD4+, CD8+ T-cell and Neutralizing Antibody Responses

2020 ◽  
Author(s):  
Adrian Rice ◽  
Mohit Verma ◽  
Annie Shin ◽  
Lise Zakin ◽  
Peter Sieling ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Surface ◽  
Immune Responses ◽  
Cd8 T Cell ◽  
Surface Expression ◽  
Antibody Responses ◽  
Cell Surface Expression ◽  
Clinical Testing ◽  
Next Generation ◽  
Cell Responses

ABSTRACTIn response to the health crisis presented by the COVID-19 pandemic, rapid development of safe and effective vaccines that elicit durable immune responses is imperative. Recent reports have raised the concern that antibodies in COVID-19 convalescent patients may not be long lasting and thus even these individuals may require vaccination. Vaccine candidates currently in clinical testing have focused on the SARS-CoV-2 wild type spike (S) protein (S-WT) as the major antigen of choice and while pre-clinical and early clinical testing have shown that S elicits an antibody response, we believe the optimal vaccine candidate should be capable of inducing robust, durable T-cell responses as well as humoral responses. We report here on a next generation bivalent human adenovirus serotype 5 (hAd5) vaccine capable of inducing immunity in patients with pre-existing adenovirus immunity, comprising both an S sequence optimized for cell surface expression (S-Fusion) and a conserved nucleocapsid (N) antigen designed to be transported to the endosomal subcellular compartment, with the potential to generate durable immune protection. Our studies suggest that this bivalent vaccine is optimized for immunogenicity as evidenced by the following findings: (i) The optimized S-Fusion displayed improved S receptor binding domain (RBD) cell surface expression compared to S-WT where little surface expression was detected; (ii) the expressed RBD from S-Fusion retained conformational integrity and recognition by ACE2-Fc; (iii) the viral N protein modified with an enhanced T-cell stimulation domain (ETSD) localized to endosomal/lysosomal subcellular compartments for MHC I/II presentation; and (iv) these optimizations to S and N (S-Fusion and N-ETSD) generated enhanced de novo antigen-specific B cell and CD4+ and CD8+ T-cell responses in antigen-naive pre-clinical models. Both the T-cell and antibody immune responses to S and N demonstrated a T-helper 1 (Th1) bias. The antibody responses were neutralizing as demonstrated by two independent SARS-CoV-2 neutralization assays. Based on these findings, we are advancing this next generation bivalent hAd5 S-Fusion + N-ETSD vaccine as our lead clinical candidate to test for its ability to provide robust, durable cell-mediated and humoral immunity against SARS-CoV-2 infection. Further studies are ongoing to explore utilizing this vaccine construct in oral, intranasal, and sublingual formulations to induce mucosal immunity in addition to cell-mediated and humoral immunity. The ultimate goal of an ideal COVID-19 vaccine is to generate long-term T and B cell memory.

Inhibition of Interleukin-2 Synthesis and Interleukin-2 Receptor α Expression on T Cells by a Cell-Free Factor Derived from a CD4+ Regulatory T Cell Clone

1993 ◽  
Vol 68 (3) ◽  
pp. 256-262 ◽  
Author(s):  
Takashi Okino ◽  
Nitya G. Chakraborty ◽  
Paul Stabach ◽  
Daniel R. Twardzik ◽  
Steven J. Padula ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cell ◽  
Cell Clone ◽  
Interleukin 2 ◽  
Interleukin 2 Receptor ◽  
T Cell Clone ◽  
A Cell

Leukemia-Reactive Virus-Specific T Cells Generated by T Cell Receptor (TCR) Transfer Preserve Their Dual Specificity upon Repetitive Stimulation of the Endogenous TCR.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 136-136
Author(s):  
M.M. van Loenen ◽  
R.S. Hagedoorn ◽  
M. Hoogeboom ◽  
M.G.D. Kester ◽  
Roelof Willemze ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Repetitive Stimulation ◽  
Cell Surface Expression ◽  
Viral Antigens ◽  
Low Expression ◽  
Stimulation Of

Abstract TCR-transfer to engineer tumor-specific T cells may be a strategy for adoptive immunotherapy. For complete eradication of leukemic cells and to achieve long-term protection, potent effector T cell function and long-term T cell persistence are necessary. Therefore, we propose to use virus specific T cells for TCR transfer since such engineered dual specific T cells can be triggered via their endogenous TCR by latent presence of viral antigens, improving their long-term persistence. We have previously shown that virus specific T cells can be redirected towards anti-leukemic reactivity by transfer of the hematopoietic minor histocompatibility antigen HA-2 specific TCR (HA-2-TCR). The TCR-transferred virus specific T cells showed differences in TCR cell surface make up, which was stable for months after repetitive non-specific TCR triggering. The T cells expressed either both TCRs intermediately at the cell surface, or the endogenous TCR was highly expressed with a low expression of the introduced TCR, or the introduced TCR was highly expressed with a low expression of the endogenous TCR. It may be anticipated that frequent encounter with viral antigens in vivo leads to selective outgrowth of TCR-transferred dual specific T cells with high expression of the endogenous viral specific TCR but low expression of the introduced tumor specific TCR, resulting in reduced anti-leukemic reactivity. To address this issue, we generated CMVA2-specific T cells transduced with the HA-2-TCR. This resulted in dual specific cells with different TCR cell surface make up. The dual specific T cells were repetitively stimulated specifically either via their endogenous virus specific TCR or via the introduced HA-2 specific TCR. In time, the cell surface expression of the endogenous and introduced TCRs as measured with CMVA2 and HA-2A2 tetramers diverged. Repetitive stimulation of the endogenous TCR skewed the dual specific T cells towards a cell population that predominantly expressed the endogenous TCR. In contrast, repetitive stimulation of the introduced TCR skewed the cells towards T cells that predominantly expressed the introduced TCR. However, this divergence in tetramer stainings was shown to quickly revert after a single stimulation via the other TCR. To study whether this divergence was the result of a difference in TCR cell surface distribution or of selective outgrowth of different T cells, T cells were sorted that predominantly expressed either the endogenous or the introduced TCR. These cells were subsequently stimulated on the endogenous or introduced TCR, and compared regarding TCR cell surface expression and functional activity. Directly after sorting dual specific T cells preferentially expressing the endogenous TCR were still reactive against HA-2+ target cells, although the reactivity was reduced compared to cells preferentially expressing the introduced TCR. However, when restimulated on the introduced HA-2-TCR, the dual specific T cells expanded antigen specifically, and reverted within several days into cells with high expression of the introduced TCR that exerted potent HA-2 specific anti-leukemic effector functions. In conclusion, we demonstrate that these dual specific T cells are likely to persist in vivo due to repetitive encounter with viral antigens with preservation of anti-leukemic effector function. Moreover, in vivo exposure to the tumor associated antigen will further enhance the relevant specificity.

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