Impact of Regulatory T Cells on Antigen Specific T Cell Response Using Recombinant Chimeric T Cell Receptors In Vivo.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5475-5475
Author(s):  
David M. Kofler ◽  
Markus Chmielewski ◽  
Heike Koehler ◽  
Tobias Riet ◽  
Patrick Schmidt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Tumor Cells ◽  
T Cell Receptors ◽  
Cell Response ◽  
Effector T Cells ◽  
T Cell Response ◽  
Cell Receptors

Abstract Recombinant T cell receptors with defined specificity against tumor cells are a promising experimental approach in the elimination of residual leukemia and lymphoma cells. It is so far unresolved whether regulatory T cells with suppressor activities impair the efficiency of cytolytic T cells grafted with a recombinant immunoreceptor. The frequency of regulatory T cells is highly increased in tumor patients and their suppressive function seems to play a role in the fail of an autologous T cell response against the malignant cells. In this study we analyzed the antigen-triggered, specific activation of receptor grafted T cells in the presence or absence of regulatory CD4+CD25high T cells. CD3+ T cells were grafted with CEA-specific immunoreceptors containing the CD3-zeta signaling domain for T cell activation. Co-cultivation of receptor grafted effector T cells together with regulatory T cells repressed proliferation of the effector cells and decreased IL-2 secretion. Secretion of IFN-gamma and IL-10 was not impaired. Interestingly, the cytotoxicity of grafted effector T cells towards CEA-expressing tumor cells was not impaired by regulatory T cells in vitro. To evaluate the relevance in vivo, we used a Crl:CD1 Nu/Nu mouse model to assess growth of CEA+ tumor cells in the presence of receptor grafted effector T cells and of regulatory T cells. Mice inoculated with tumor cells together with CD3+ effector T cells without immunoreceptor and regulatory T cells developed earlier tumors with faster growth kinetics compared to mice that were inoculated with tumor cells, CD3+ T cells and CD4+CD25- control T cells. Using effector T cells that were equipped with a recombinant CEA-specific CD3-zeta immunoreceptor, 2 of 5 mice developed a tumor in the presence of regulatory T cells while none of the mice developed a tumor in the absence of regulatory T cells. Taken together, regulatory T cells obviously impair an antigen-specific, anti-tumor T cell attack in vivo. This seems to be due to repression of proliferation of the effector T cells and not to diminished cytotoxicity. These findings have major impact on the design of clinical studies involving adoptively transferred effector T cells.

scholarly journals Superresolution imaging reveals nanometer- and micrometer-scale spatial distributions of T-cell receptors in lymph nodes

2016 ◽  
Vol 113 (26) ◽  
pp. 7201-7206 ◽  
Author(s):  
Ying S. Hu ◽  
Hu Cang ◽  
Björn F. Lillemeier
Keyword(s):  
T Cells ◽  
Plasma Membrane ◽  
T Cell ◽  
Lymph Nodes ◽  
T Cell Activation ◽  
T Cell Receptors ◽  
Cell Activation ◽  
Cell Receptors ◽  
Micrometer Scale

T cells become activated when T-cell receptors (TCRs) recognize agonist peptides bound to major histocompatibility complex molecules on antigen-presenting cells. T-cell activation critically relies on the spatiotemporal arrangements of TCRs on the plasma membrane. However, the molecular organizations of TCRs on lymph node-resident T cells have not yet been determined, owing to the diffraction limit of light. Here we visualized nanometer- and micrometer-scale TCR distributions in lymph nodes by light sheet direct stochastic optical reconstruction microscopy (dSTORM) and structured illumination microscopy (SIM). This dSTORM and SIM approach provides the first evidence, to our knowledge, of multiscale reorganization of TCRs during in vivo immune responses. We observed nanometer-scale plasma membrane domains, known as protein islands, on naïve T cells. These protein islands were enriched within micrometer-sized surface areas that we call territories. In vivo T-cell activation caused the TCR territories to contract, leading to the coalescence of protein islands and formation of stable TCR microclusters.

scholarly journals Adoptive cellular therapy enhances the helper T cell response and reduces the number of regulatory T cells

2011 ◽  
Vol 2 (4) ◽  
pp. 737-743 ◽  
Author(s):  
TAKESHI ISHIKAWA ◽  
SATOSHI KOKURA ◽  
NAOYUKI SAKAMOTO ◽  
TSUGUHIRO MATSUMOTO ◽  
JUN FUNAKI ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Response ◽  
Cellular Therapy ◽  
T Cell Response ◽  
Helper T Cell ◽  
Adoptive Cellular Therapy

scholarly journals Antiviral cytotoxic T cell response induced by in vivo priming with a free synthetic peptide.

1990 ◽  
Vol 171 (5) ◽  
pp. 1815-1820 ◽  
Author(s):  
P Aichele ◽  
H Hengartner ◽  
R M Zinkernagel ◽  
M Schulz
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Lymphocytic Choriomeningitis ◽  
Effector T Cells ◽  
T Cell Response ◽  
Class I ◽  
Cytotoxic T Cell ◽  
Effector T Cell

Induction in vivo of antiviral cytotoxic T cell response was achieved in a MHC class I-dependent fashion by immunizing mice three times with a free unmodified 15-mer peptide derived from the nucleoprotein of lymphocytic choriomeningitis virus in IFA. The effector T cells are CD8+, restricted to the class I Ld allele of the analyzed mouse strain, and are specific both at the level of secondary restimulation in vitro and at the effector T cell level. These results suggest that cocktails of viral peptides may be used as antiviral T cell vaccines.

scholarly journals Regulatory T Cells Shape the Resident Memory T Cell Response to Virus Infection in the Tissues

2013 ◽  
Vol 192 (2) ◽  
pp. 683-690 ◽  
Author(s):  
Jessica B. Graham ◽  
Andreia Da Costa ◽  
Jennifer M. Lund
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Infection ◽  
Regulatory T Cells ◽  
Cell Response ◽  
T Cell Response ◽  
Memory T Cell

Loss of EBV-Specific CD4+T Cells during Progression to EBV-Related AIDS Non-Hodgkin Lymphoma: Restoration by Highly Active Antiretroviral Therapy (HAART).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3110-3110
Author(s):  
Erwan R. Piriou ◽  
Christine Jansen ◽  
Karel van Dort ◽  
Iris De Cuyper ◽  
Nening M. Nanlohy ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Cd4 T Cells ◽  
Antigen Processing ◽  
Ex Vivo ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Cell Numbers

Abstract Objective: EBV-specific CD8+ T cells have been extensively studied in various settings, and appear to play a major role in the control of EBV-related malignancies. In contrast, it is still unclear whether EBV-specific CD4+ T cells play a role in vivo. To study this question, an assay was developed to measure the CD4+ T-cell response towards two EBV antigens, in both healthy (n=14) and HIV-infected subjects (n=23). In addition, both HAART-treated (n=12) and untreated HIV+ individuals (n=14) - including progressors to EBV-related lymphoma - were studied longitudinally. Methods: EBV-specific CD4+ T cells were stimulated with peptide pools from latent protein EBNA1 and lytic protein BZLF1, and detected by measurement of IFNg-production. Results: After direct ex vivo stimulation, EBNA1 or BZLF1-specific IFNg- (and/or IL2) producing CD4+ T cell numbers were low, and measurable in less than half of the subjects studied (either HIV- and HIV+). Therefore, PBMC were cultured for 12 days in the presence of peptides and IL2 (from day 3), and then restimulated with peptides, allowing specific and reproducible expansion of EBV-specific CD4+ T cells, independent of HLA type and ex vivo antigen processing. Interestingly, numbers of EBV-specific CD4+ T cells inversely correlated with EBV viral load, implying an important role for EBV-specific CD4+ T cells in the control of EBV in vivo. Untreated HIV-infected individuals had a lower CD4+ T cell response to EBNA1 and BZLF1 as compared to healthy EBV carriers and HAART-treated HIV+ subjects. In longitudinal samples, EBNA1-specific, but not BZLF1-specific T-cell numbers increased after HAART, while EBV load was not affected by treatment. In all the progressors to EBV-related lymphoma, EBV-specific CD4+ T cells were lost at least 24 months before lymphoma diagnosis. Conclusions: Both cross-sectional and longitudinal data suggest an important role for EBV-specific CD4+ T cells in the control of EBV-related malignancies. Furthermore, it seems that HAART treatment leads to recovery of EBNA1-specific, but not BZLF1-specific CD4+ T-cell responses, implying changes in the latency pattern of EBV, despite an unaltered cell-associated EBV DNA load. Thus, early HAART treatment might prevent loss of specific CD4+ T-cell help and progression to NHL.

Tumor-Targeted Human CD4+ CD25hi Regulatory T Cells Effectively Inhibit T Cell –mediated Rejection of CD19+ Tumors in An in Vivo xenotransplant Tumor Model

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3901-3901
Author(s):  
James Lee ◽  
Michel Sadelain ◽  
Renier J. Brentjens
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
B Cell ◽  
Clinical Setting ◽  
Effector T Cells ◽  
Effector T Cell ◽  
Human T Cells ◽  
Anti Tumor Activity

Abstract The genetic targeting of human T cells to selected tumor antigens offers a novel means to investigate human immunobiology and treat cancer. T cells may be genetically modified to target specific antigens through the introduction of genes encoding chimeric antigen receptors (CARs). We have previously demonstrated that human T cells targeted in this manner to the CD19 antigen, expressed on normal B cells as well as most B cell tumors, eradicate systemic human CD19+ B cell malignancies in SCID-Beige mice. However, in the clinical setting, the anti-tumor efficacy of these T cells may be impaired by endogenous suppressive elements of the host immune system, including CD4+ CD25hi Foxp3+ regulatory T cells (Tregs). Significantly, Tregs are often increased in the blood and infiltrate the tumor of cancer patients which has been correlated with poor patient outcome and ineffective anti-tumor immunity. In order to study the in vivo impact of Tregs on adoptive therapy with CD19 targeted effector T cells, we developed a murine model wherein human Tregs, similarly targeted to the tumor, are infused prior to adoptive transfer of targeted cytotoxic T cells. To do so, we initially isolated natural Tregs from healthy donor peripheral blood mononuclear cells. Isolated Tregs were subsequently modified to express CARs through retroviral gene transfer. Subsequently, CAR+ Tregs were rapidly expanded either by activation on NIH-3T3 fibroblasts modified to express CD19 and the CD80 costimulatory ligand (3T3(CD19/CD80)), or non-specifically using CD3/CD28 antibodycoated magnetic beads. Expanded CAR+ Tregs exhibited potent suppressive function in vitro inhibiting both effector T cell proliferation as well as cytotoxicity. In vivo, CAR+ Tregs specifically traffic to established tumor in SCID-Beige mice. Significantly, injection of CD19-targeted Tregs into SCID-Beige mice bearing established human CD19+ tumors at 24 hours prior to infusion with CD19-targeted effector T cells, completely abrogated effector T cell function even at Treg:Teff ratios as low as 1:8. We further found that full suppression was dependant both on Treg localization to the tumor site as well as in vivo activation through the CAR. Finally, we show that a pre-conditioning regimen with low-dose cyclophosphamide, which failed to eradicate tumor, was able to reverse the CAR+ Treg mediated inhibition and restore the anti-tumor activity by the targeted effector T cells. In conclusion, we have developed a robust model ideally suited to the study of in vivo Treg-Teff interactions. Furthermore, the data generated from this model to date have significant implications with respect to the application of adoptive T cell therapies in the clinical setting. Namely, the presence of endogenous Tregs at the site of tumor is likely to significantly compromise the anti-tumor activity of adoptively transferred tumor targeted T cells. This inhibition may be reversed by preconditioning regimens designed to eradicate endogenous Tregs. The findings presented here should be considered in the design of future clinical trials utilizing T cell-based adoptive therapies of cancer.

Turning Tregs into class I suppressors

Blood ◽  
2012 ◽  
Vol 119 (15) ◽  
pp. 3373-3374 ◽  
Author(s):  
Terrence L. Geiger
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Mhc Class I ◽  
T Cell Receptors ◽  
Class I ◽  
Cell Receptors ◽  
Tcr Affinity

In this issue of Blood, Plesa et al demonstrate that human Foxp3+ regulatory T cells can be redirected using MHC class I–restricted T-cell receptors (TCRs), showing a surprising lack of correlation of TCR affinity and their suppressive potency.1

scholarly journals Role of viral infectivity in the induction of influenza virus-specific cytotoxic T cells.

1978 ◽  
Vol 147 (4) ◽  
pp. 1236-1252 ◽  
Author(s):  
T J Braciale ◽  
K L Yap
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Cell Response ◽  
Infectious Virus ◽  
Cytotoxic T Cells ◽  
T Cell Response ◽  
Cytotoxic T Cell

This report examines the requirement for infectious virus in the induction of influenza virus-specific cytotoxic T cells. Infectious influenza virus was found to be highly efficient at generating both primary and secondary cytotoxic T-cell response in vivo. Inactivated influenza virus however, failed to stimulate a detectable cytotoxic T-cell response in vivo even at immunizing doses 10(5)-10(6)-fold higher than the minimum stimulatory dose of infectious virus. Likewise inactivated virus failed to sensitize target cells for T cell-mediated lysis in vitro but could stimulate a specific cytotoxic response from primed cells in vitro. Possible requirements for the induction of virus-specific cytotoxic T-cell responses are discussed in light of these observations and those of other investigators.

scholarly journals Novel Multi-Target Immunosuppressive Approach for Treatment of Severe Aplastic Anemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3611-3611 ◽  
Author(s):  
Kyle Blaine Russell ◽  
Brandon P Theall ◽  
Lisandra Hernandez ◽  
Hannah M Wavering ◽  
Vesna Jurecic ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Autoimmune Diseases ◽  
Aplastic Anemia ◽  
Effector T Cells ◽  
Prolonged Treatment ◽  
Effector T Cell ◽  
New Therapy

Abstract Aplastic Anemia (AA) is an immune-mediated form of acquired bone marrow failure (BMF), which is life-threatening in its severe form (SAA). Fundamental pathological features of AA include development and expansion of auto-reactive effector T cells, effector T cell-mediated apoptosis of all hematopoietic cells (including progenitors and hematopoietic stem cells (HSCs)), BM aplasia, pancytopenia, depletion of HSCs, and severe reduction and functional impairment of regulatory T cells (Tregs). Current standard treatments for AA include: (1) immuno-suppressive therapy (IST) with cyclosporine A (CyA) and anti-thymocyte globulin (ATG) which targets all T cells, and (2) allogeneic or matched unrelated donor BM transplant. While IST remains a standard treatment modality, it is not very effective in treating already ongoing and relapsed AA or SAA. There is really no effective therapy for patients with refractory and relapsed AA who are ineligible for BMT. Among different pathophysiological features of AA, IST targets only the effector T cells, and is much more effective in the early than later stages of AA. Moreover, the combination of IST with other immunosuppressive agents (mycophenolate mofetil, sirolimus etc.) or growth factors does not improve the response or survival of AA patients. Since the incidence of AA is on the rise, there is an urgent need for more efficient new therapies that can attenuate the progression and severity of AA in patients with refractory and relapsed AA who are waiting for or are not candidates for BMT. The complex immune and hematological pathophysiology of AA requires new multipurpose treatment approaches. Accumulating evidence shows that β2 integrin CD11b/CD18 (Mac-1) negatively regulates T cell responses and activation, attenuates inflammation, and facilitates the maintenance of tolerance to self-antigens. For example, activated Mac-1 significantly reduces the T cell-activating capacity of dendritic cells (DCs), represses DC cross-priming of cytotoxic T cells, negatively regulates NK cell activation and function, suppresses differentiation of Th17 T cells which are associated with AA and other autoimmune diseases, ameliorates experimental autoimmune hepatitis, and negatively regulates BCR signaling and maintains autoreactive B cell tolerance. For that reason, Mac-1 is an attractive molecular target for new immune-modulating therapies of autoimmune diseases. Using the clinically relevant mouse SAA model we have evaluated the therapeutic efficacy of Leukadherins (LA1-LA3), novel small molecule agonists and activators of Mac-1, as a novel multipurpose immunosuppressive and anti-inflammatory approach to treat AA. The present studies have demonstrated that administration of LA1 safely and significantly (1) suppresses expansion of effector T cells, (2) decreases effector T cell-mediated apoptosis of target BM cells, (2) reduces BM aplasia, (3) minimalizes the loss of HSCs and progenitors, and (4) attenuates the severity of SAA. Furthermore, prolonged treatment of developing SAA with LA1 has therapeutic effects since it not only attenuates the progression and severity of SAA, but also converts otherwise fatal SAA into a survivable disease in mouse SAA models. To begin to address mechanism for these findings we found that LA1 treatment significantly reduces the antigen presenting capacity and T cell activating capacity of DCs. Importantly, in vivo LA1 treatment significantly increases the population of regulatory T cells (Tregs) which may also contribute to the above effects of LA1 on SAA. Simultaneous targeting of multiple pathophysiological features of AA underscores the clinically relevant potential of LA1 treatment as a novel promising multi-target immunosuppressive therapy that can safely and efficiently attenuate the severity of AA and reduce the need for BMT. We are also further evaluating the potential of LA1 treatment combined with IST or in vivo Treg expansion approaches (low dose rIL-2 therapy) to safely and more effectively attenuate the progression and severity of AA in pre-clinical mouse SAA models. These studies will provide an important platform for further translational and clinical testing of LAs as: (1) New therapy to manage ongoing AA in patients who are not responding to IST and are not candidates for BMT, (2) New therapy for relapsed AA, and/or (3) Adjuvant therapy for AA patients who are undergoing IST and are awaiting BM transplant. Disclosures Levy: Allergan: Consultancy.

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