scholarly journals Enhancement of an anti-tumor immune response by transient blockade of central T cell tolerance

2014 ◽  
Vol 211 (5) ◽  
pp. 761-768 ◽  
Author(s):  
Imran S. Khan ◽  
Maria L. Mouchess ◽  
Meng-Lei Zhu ◽  
Bridget Conley ◽  
Kayla J. Fasano ◽  
...  
Keyword(s):  
T Cells ◽  
Ectopic Expression ◽  
Therapeutic Benefit ◽  
Effector T Cells ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Specific Effector ◽  
Medullary Thymic Epithelial Cells ◽  
Specific Antigens

Thymic central tolerance is a critical process that prevents autoimmunity but also presents a challenge to the generation of anti-tumor immune responses. Medullary thymic epithelial cells (mTECs) eliminate self-reactive T cells by displaying a diverse repertoire of tissue-specific antigens (TSAs) that are also shared by tumors. Therefore, while protecting against autoimmunity, mTECs simultaneously limit the generation of tumor-specific effector T cells by expressing tumor self-antigens. This ectopic expression of TSAs largely depends on autoimmune regulator (Aire), which is expressed in mature mTECs. Thus, therapies to deplete Aire-expressing mTECs represent an attractive strategy to increase the pool of tumor-specific effector T cells. Recent work has implicated the TNF family members RANK and RANK-Ligand (RANKL) in the development of Aire-expressing mTECs. We show that in vivo RANKL blockade selectively and transiently depletes Aire and TSA expression in the thymus to create a window of defective negative selection. Furthermore, we demonstrate that RANKL blockade can rescue melanoma-specific T cells from thymic deletion and that persistence of these tumor-specific effector T cells promoted increased host survival in response to tumor challenge. These results indicate that modulating central tolerance through RANKL can alter thymic output and potentially provide therapeutic benefit by enhancing anti-tumor immunity.

scholarly journals Central Tolerance to Tissue-specific Antigens Mediated by Direct and Indirect Antigen Presentation

2004 ◽  
Vol 200 (8) ◽  
pp. 1039-1049 ◽  
Author(s):  
Alena M. Gallegos ◽  
Michael J. Bevan
Keyword(s):  
T Cells ◽  
Antigen Presentation ◽  
Cd8 T Cells ◽  
Thymic Epithelial Cells ◽  
Clonal Deletion ◽  
Autoreactive T Cells ◽  
Tissue Specific ◽  
Central Tolerance ◽  
Cross Presentation ◽  
Specific Antigens

Intrathymic expression of tissue-specific antigens (TSAs) by medullary thymic epithelial cells (Mtecs) leads to deletion of autoreactive T cells. However, because Mtecs are known to be poor antigen-presenting cells (APCs) for tolerance to ubiquitous antigens, and very few Mtecs express a given TSA, it was unclear if central tolerance to TSA was induced directly by Mtec antigen presentation or indirectly by thymic bone marrow (BM)-derived cells via cross-presentation. We show that professional BM-derived APCs acquire TSAs from Mtecs and delete autoreactive CD8 and CD4 T cells. Although direct antigen presentation by Mtecs did not delete the CD4 T cell population tested in this study, Mtec presentation efficiently deleted both monoclonal and polyclonal populations of CD8 T cells. For developing CD8 T cells, deletion by BM-derived APC and by Mtec presentation occurred abruptly at the transitional, CD4high CD8low TCRintermediate stage, presumably as the cells transit from the cortex to the medulla. These studies reveal a cooperative relationship between Mtecs and BM-derived cells in thymic elimination of autoreactive T cells. Although Mtecs synthesize TSAs and delete a subset of autoreactive T cells, BM-derived cells extend the range of clonal deletion by cross-presenting antigen captured from Mtecs.

Requirements for Retroviral Targeting of a Suicide Gene to Alloreactive Memory Stem T Cells for Adoptive Immunotherapy of Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2176-2176
Author(s):  
Attilio Bondanza ◽  
Lothar Hambach ◽  
Shin Kaneko ◽  
Sara Mastaglio ◽  
Bart Nijmeijer ◽  
...  
Keyword(s):  
T Cells ◽  
Memory T Cells ◽  
Suicide Gene ◽  
Effector T Cells ◽  
Donor T Cells ◽  
Specific Effector ◽  
Ifn Γ ◽  
Homeostatic Cytokines

Abstract In a phase I/II clinical trial investigating the prophylactic infusion of suicide gene-modified donor T cells in the context of haploidentical hemopoietic cell transplantation (haplo-HCT) for the treatment of high-risk leukemia, we observed a rapid and effective immune reconstitution. After activation with anti-CD3 antibodies, genetic modification of donor T cells was accomplished with a retroviral vector encoding for the Herpes Simplex thymidine kinase (TK). In vitro before infusion and in vivo at immune reconstitution, TK+ cells displayed an effector memory (EM) phenotype (CD45RA–CD62L−, CD28±CD27+, IL-2±IFN–γ+). The graft-versus-leukemia (GvL) effect was substantial in patients transplanted in remission, but failed to cure patients in relapse. Gene targeting with retroviral vectors is limited to memory T cells. Central memory (CM) T cells (CD45RA–CD62L+, CD28+CD27+, IL-2+IFN-γ±) share many characteristics with stem cells, namely the ability to self-renew and to differentiate into a progeny of effector cells. EM TK+ cells have a reduced alloreactivity. Recently, it has been proposed that alloreactivity may be confined to memory T cells with stem cell-features. Since alloantigens are the target not only of graft-versus-host disease (GvHD), but also of the GvL effect, crucial to the success of the strategy is the suicide gene-modification of this subset of memory T cells. We found that addition of CD28 costimulation on cell-sized beads and the use of homeostatic cytokines, such as IL-7 and IL-15, generates central memory (CM) TK+ cells. CM TK+ cells are highly alloreactive, both in vitro and in vivo in a humanized animal model of GvHD based on the grafting of human skin onto NOD/scid mice. Interestingly, CM TK+ cells express the IL7Rα, a marker associated with the stem cell-features of memory T cells. Moreover, IL7Rα expression is maintained after stimulation with alloantigens. Stimulation of CM, but not of EM TK+ cells with autologous dendritic cells pulsed with restricted peptides from the minor histocompatibility alloantigen (mHag) HA-1 or H-Y efficiently induces mHag-specific effector T cells that lyse natural ligand expressing HLA-A2+ targets. TK+ mHag-specific effector T cells also lysed mHag+HLA-A2+ leukemic cells and, when infused in conditioned NOD/scid mice harboring human leukemia, significantly delayed disease progression. Altogether, these data suggest that optimal T-cell receptor triggering and homeostatic cytokines are required for retroviral targeting of a suicide gene to alloreactive memory stem T cells and warrant their use for a safe and powerful GvL effect.

Immunotherapy of Acute MYELOID LEUKEMIA: ANTI-LEUKEMIC EFFECTS by Unprimed or Primed, Selected or Unselected Effector T-CELLS.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 5122-5122
Author(s):  
Helga Schmetzer ◽  
Friedhelm R Schuster ◽  
Raymund Buhmann ◽  
Markus Freudenreich ◽  
Georg Doessinger ◽  
...  
Keyword(s):  
T Cells ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Prognostic Significance ◽  
Therapeutic Benefit ◽  
Effector T Cells ◽  
Leukemic Cells ◽  
Cell Reactivity ◽  
High Concentrations

Abstract Abstract 5122 T-cells are the most important mediators of antileukemic reactions after allogeneic stemcelltransplantation (SCT) or donorlymphocyte-infusions (DLI) in patients (pts) with myeloid leukemias (AML,MDS), although relapses occur. Presentation of leukemic antigens (LAA) is improved by conversion of leukemic cells to leukemia derived DC (DCleu). Our hypothesis is, that myeloid blasts convert in vivo spontaneously to DCleu and prime CTL; moreover DCleu can be generated ex vivo from blasts and be used to prime T-cells enabling the generation of leukemia-specific CTL. Therefore (unprimed or primed) antileukemic effector T-cells have to be identified, characterized, optimized or selected. Results 1) Blast- and DC-characterization: Blasts can be characterized by blast phenotypes or LAA-RNA-PCR(WT1,PR1 or PRAME).An LAA-overexpression was found in 70-94% of 88AML-samples compared to healthy controls. Ex vivo DCleu can regularly be generated independent from karyotypes and quantified in every AML-case and used to prime T-cells(Schmetzer 2005-2009). 2) Effectorcell characterization : a)In 6 patients after preemptive DLI-therapy between 0.1 and 0.5% LAA-specific T-cells with a highly Vβ-restricted T-cellprofil were found(Tetramer/Spectratyping). B)Compared to unprimed T-cells (with no or low antileukemic ex vivo function) selected from a patient after SCT IFNg-selected unprimed and even more primed T-cells have an improved antileukemic function compared to non-IFNg-selected primed T-cells. C) DC-priming (more than blast-priming) increases the antileukemic T-cell reactivity (shown in 20 cases) and is associated with highest Vβ-restriction, but is not in every case successful C) By spectratyping identical clone was found after DC-priming ex vivo and in vivo prepared from patient proving the value of DC-culturing for ‘simulating’ in vivo reactions. 3)Predictive and prognostic significance: a)Composition of DC-subtypes (high proportions of mature and leukemia-derived DC) and of T-cells (ratios>1 of CD4:CD8 and CD45RO:CD45RA)and microenvironment (high concentrations of CXCL8 and CCL2 in DC-culture supernatans,IL6 and IFNg in DC/T-MLC-supernatans) arepredictive for effectful antileukemic functionalityof primed T-cells b) Composition of DC-subtypes (high proportions of mature, leukemia-derived DC and convertibility of blasts to DC) predicts the clinical response to immunotherapy (SCT (n=18) or DLI-relapse therapy (n=17)):cases with higher proportions of mature DC/ DCleu /better blastconvertibility to DCleu had a higher chance to respond to immunotherapy (SCT/DLI) and had an improved overall survival. In summary blasts can be characterized (LAA/blast phenotype) and DC/DCleu be generated in any given case independent from karyotype. A DC priming of T cells improves the antileukemic CTL, but not in every case. The composition of DC and T cells and the microenvironment in MLC are predictive for the ex vivo lytic efficiency of DC-primed T cells and for patients' response to immunotherapy (SCT or DLI). Effector T-cells can be identified, characterized or selected by their Vβ-profil, their LAA-specifity or IFNg-release (before or after blast- or DC-priming). Although the reactive differences or the therapeutic benefit of those different T-cellsubsets are not clear at the moment we hope to contribute to understand biological mechanisms behind cytotoxic reactions, to identify reactive T-cells (and identify best stemcell donors), to learn about escape mechanisms and to develop adoptive immunotherapies with specific, antileukemia directed T-cells without side effects. Disclosures No relevant conflicts of interest to declare.

scholarly journals Regulation of specific cell-mediated cytotoxic response against SV40-induced tumor associated antigens by depletion of suppressor T cells with cyclophosphamide in mice.

1979 ◽  
Vol 149 (3) ◽  
pp. 774-779 ◽  
Author(s):  
M Glaser
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Effector T Cells ◽  
Specific Cell ◽  
51Cr Release ◽  
Tumor Associated Antigens ◽  
Specific Effector ◽  
Release Assay

When cyclophosphamide was administered to mice before immunization with syngeneic SV40 transformed cells, the specific immune response elicited, as was measured by in vitro 51Cr release assay was stronger and lasted longer when compared to the response generated in noncyclophosphamide-treated mice. The augmentation effect of the drug was dependent on cyclophosphamide concentration being optimal at 100 mg/kg and on the time of drug administration in relation to antigen immunization being optimal at 2 d before antigen administration. Transfer of T cells from normal syngeneic mice to drug-treated animals abolished the cyclophosphamide-induced augmentation of immune response. These results implied that cyclophosphamide sensitive T cells suppressed the in vivo generation of specific effector T cells against SV40-induced tumor-associated antigens.

scholarly journals Selective involution of thymic medulla by cyclosporine A with a decrease of mature thymic epithelia, XCR1+ dendritic cells, and epithelium-free areas containing Foxp3+ thymic regulatory T cells

2021 ◽  
Author(s):  
Yasushi Sawanobori ◽  
Yusuke Kitazawa ◽  
Hisashi Ueta ◽  
Kenjiro Matsuno ◽  
Nobuko Tokuda
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cyclosporine A ◽  
Immunosuppressive Drugs ◽  
Cell System ◽  
Thymic Epithelial Cells ◽  
Complex Molecules ◽  
Single Positive ◽  
Thymic Medulla ◽  
Medullary Thymic Epithelial Cells

AbstractImmunosuppressive drugs such as cyclosporine A (CSA) can disrupt thymic structure and functions, ultimately inducing syngeneic/autologous graft-versus-host disease together with involuted medullas. To elucidate the effects of CSA on the thymus more precisely, we analyzed the effects of CSA on the thymus and T cell system using rats. In addition to confirming the phenomena already reported, we newly found that the proportion of recent thymic emigrants also greatly decreased, suggesting impaired supply. Immunohistologically, the medullary thymic epithelial cells (mTECs) presented with a relative decrease in the subset with a competent phenotype and downregulation of class II major histocompatibility complex molecules. In control rats, thymic dendritic cells (DCs) comprised two subsets, XCR1+SIRP1α−CD4− and XCR1−SIRP1α+CD4+. The former had a tendency to selectively localize in the previously-reported epithelium-containing areas of the rat medullas, and the number was significantly reduced by CSA treatment. The epithelium-free areas, another unique domains in the rat medullas, contained significantly more Foxp3+ thymic Tregs. With CSA treatment, the epithelium-free areas presented strong involution, and the number and distribution of Tregs in the medulla were greatly reduced. These results suggest that CSA inhibits the production of single-positive thymocytes, including Tregs, and disturbs the microenvironment of the thymic medulla, with a decrease of the competent mTECs and disorganization of epithelium-free areas and DC subsets, leading to a generation of autoreactive T cells with selective medullary involution.

scholarly journals Effect of Coxsackievirus B4 Infection on the Thymus: Elucidating Its Role in the Pathogenesis of Type 1 Diabetes

2021 ◽  
Vol 9 (6) ◽  
pp. 1177
Author(s):  
Abdulaziz Alhazmi ◽  
Magloire Pandoua Nekoua ◽  
Hélène Michaux ◽  
Famara Sane ◽  
Aymen Halouani ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Viral Infections ◽  
Lymphoid Organ ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Coxsackievirus B4

The thymus gland is a primary lymphoid organ for T-cell development. Various viral infections can result in disturbance of thymic functions. Medullary thymic epithelial cells (mTECs) are important for the negative selection of self-reactive T-cells to ensure central tolerance. Insulin-like growth factor 2 (IGF2) is the dominant self-peptide of the insulin family expressed in mTECs and plays a crucial role in the intra-thymic programing of central tolerance to insulin-secreting islet β-cells. Coxsackievirus B4 (CVB4) can infect and persist in the thymus of humans and mice, thus hampering the T-cell maturation and differentiation process. The modulation of IGF2 expression and protein synthesis during a CVB4 infection has been observed in vitro and in vivo in mouse models. The effect of CVB4 infections on human and mouse fetal thymus has been studied in vitro. Moreover, following the inoculation of CVB4 in pregnant mice, the thymic function in the fetus and offspring was disturbed. A defect in the intra-thymic expression of self-peptides by mTECs may be triggered by CVB4. The effects of viral infections, especially CVB4 infection, on thymic cells and functions and their possible role in the pathogenesis of type 1 diabetes (T1D) are presented.

scholarly journals H-2 restriction of virus-specific T-cell-mediated effector functions in vivo. II. Adoptive transfer of delayed-type hypersensitivity to murine lymphocytic choriomeningits virus is restriced by the K and D region of H-2.

1976 ◽  
Vol 144 (3) ◽  
pp. 776-787 ◽  
Author(s):  
R M Zinkernagel
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Transfer ◽  
Gamma Globulin ◽  
Effector T Cells ◽  
Delayed Type Hypersensitivity ◽  
T Effector Cells ◽  
Immune Lymphocytes ◽  
D Region

In mice, primary footpad swelling after local infection with lymphocytic choriomeningitis virus (LCMV) and delayed-type hypersensitivity (DTH) adoptively transferred by LCMV immune lymphocytes are T-cell dependent. Nude mice do not develop primary footpad swelling, and T-cell depletion abrogates the capacity to transfer LCMV-specific DTH. Effector T cells involved in eliciting dose-dependent DTH are virus specific in that vaccinia virus-immune lymphocytes could not elicit DTH in LCMV-infected mice. The adoptive transfer of DTH is restricted to H-2K or H-2D compatible donor-recipient combinations. Distinct from the fowl-gamma-globulin DTH model, I-region compatibility is neither necessary nor alone sufficient. Whatever the mechanisms involved in this K- or D-region associated restriction in vivo, it most likely operates at the level of T-cell recognition of "altered self" coded in K or D. T cells associated with the I region (helper T cells and DTH-T cells to fowl-gamma-globulin) are specific for soluble, defined, and inert antigens. T cells associated with the K and D region (T cells cytotoxic in vitro and in vivo for acute LCMV-infected cells, DTH effector T cells, and anti-viral T cells) are specific for infectious, multiplying virus. The fact that T-cell specificity is differentially linked with the I region or with the K and D regions of H-2 may reflect the fundamental biological differences of these antigens. Although it cannot be excluded that separate functional subclasses of T-effector cells could have self-recognizers for different cell surface structures coded in I or K and D, it is more likely that the antigen parameters determine whether T cells are specific for "altered" I or "altered" K- or D-coded structures.

scholarly journals Age-Related Changes in Thymic Central Tolerance

2021 ◽  
Vol 12 ◽  
Author(s):  
Jayashree Srinivasan ◽  
Jessica N. Lancaster ◽  
Nandini Singarapu ◽  
Laura P. Hale ◽  
Lauren I. R. Ehrlich ◽  
...  
Keyword(s):  
T Cells ◽  
Negative Selection ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Adult Transition ◽  
Treg Function ◽  
Age Related ◽  
And Function ◽  
Antigen Presenting ◽  
Age Related Changes

Thymic epithelial cells (TECs) and hematopoietic antigen presenting cells (HAPCs) in the thymus microenvironment provide essential signals to self-reactive thymocytes that induce either negative selection or generation of regulatory T cells (Treg), both of which are required to establish and maintain central tolerance throughout life. HAPCs and TECs are comprised of multiple subsets that play distinct and overlapping roles in central tolerance. Changes that occur in the composition and function of TEC and HAPC subsets across the lifespan have potential consequences for central tolerance. In keeping with this possibility, there are age-associated changes in the cellular composition and function of T cells and Treg. This review summarizes changes in T cell and Treg function during the perinatal to adult transition and in the course of normal aging, and relates these changes to age-associated alterations in thymic HAPC and TEC subsets.

414 VACCINATION WITH RAD5 CARRYING A FUSION CONSTRUCT OF PROSTATE-SPECIFIC ANTIGENS GENERATES EFFECTOR T CELLS

2011 ◽  
Vol 185 (4S) ◽  
Author(s):  
Felipe Rosso ◽  
Jeffrey Holzbeierlein ◽  
Peter Van Veldhuizen ◽  
Dev Karan
Keyword(s):  
T Cells ◽  
Effector T Cells ◽  
Fusion Construct ◽  
Specific Antigens ◽  
Prostate Specific Antigens
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