MEMORY T CELLS INDUCED BY T CELL DELETION: THEIR IN VITRO FUNCTION AND EFFECT ON SKIN ALLOGRAFT SURVIVAL IN COMPARISON TO REJECTION-INDUCED MEMORY T CELLS.

2006 ◽  
Vol 82 (Suppl 2) ◽  
pp. 751
Author(s):  
&NA;
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Allograft Survival ◽  
Skin Allograft ◽  
Cell Deletion

scholarly journals Endogenous dendritic cells mediate the effects of intravenously injected therapeutic immunosuppressive dendritic cells in transplantation

Blood ◽  
2010 ◽  
Vol 116 (15) ◽  
pp. 2694-2705 ◽  
Author(s):  
Sherrie J. Divito ◽  
Zhiliang Wang ◽  
William J. Shufesky ◽  
Quan Liu ◽  
Olga A. Tkacheva ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Indirect Pathway ◽  
Allograft Survival ◽  
Complex Molecules ◽  
Cell Responses ◽  
Histocompatibility Complex

Abstract The prevailing idea regarding the mechanism(s) by which therapeutic immunosuppressive dendritic cells (DCs) restrain alloimmunity is based on the concept that they interact directly with antidonor T cells, inducing anergy, deletion, and/or regulation. However, this idea has not been tested in vivo. Using prototypic in vitro–generated maturation-resistant (MR) DCs, we demonstrate that once MR-DCs carrying donor antigen (Ag) are administered intravenously, they decrease the direct and indirect pathway T-cell responses and prolong heart allograft survival but fail to directly regulate T cells in vivo. Rather, injected MR-DCs are short-lived and reprocessed by recipient DCs for presentation to indirect pathway CD4+ T cells, resulting in abortive activation and deletion without detrimental effect on the number of indirect CD4+ FoxP3+ T cells, thus increasing the regulatory to effector T cell relative percentage. The effect on the antidonor response was independent of the method used to generate therapeutic DCs or their viability; and in accordance with the idea that recipient Ag-presenting cells mediate the effects of therapeutic DCs in transplantation, prolongation of allograft survival was achieved using donor apoptotic MR-DCs or those lacking surface major histocompatibility complex molecules. We therefore conclude that therapeutic DCs function as Ag-transporting cells rather than Ag-presenting cells to prolong allograft survival.

scholarly journals CD40L+ CD4+ memory T cells migrate in a CD62P-dependent fashion into reactive lymph nodes and license dendritic cells for T cell priming

2008 ◽  
Vol 205 (11) ◽  
pp. 2561-2574 ◽  
Author(s):  
Alfonso Martín-Fontecha ◽  
Dirk Baumjohann ◽  
Greta Guarda ◽  
Andrea Reboldi ◽  
Miroslav Hons ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Memory T Cells ◽  
Effector Memory ◽  
High Endothelial Venules ◽  
T Cell Priming ◽  
Dc Maturation

There is growing evidence that the maturation state of dendritic cells (DCs) is a critical parameter determining the balance between tolerance and immunity. We report that mouse CD4+ effector memory T (TEM) cells, but not naive or central memory T cells, constitutively expressed CD40L at levels sufficient to induce DC maturation in vitro and in vivo in the absence of antigenic stimulation. CD4+ TEM cells were excluded from resting lymph nodes but migrated in a CD62P-dependent fashion into reactive lymph nodes that were induced to express CD62P, in a transient or sustained fashion, on high endothelial venules. Trafficking of CD4+ TEM cells into chronic reactive lymph nodes maintained resident DCs in a mature state and promoted naive T cell responses and experimental autoimmune encephalomyelitis (EAE) to antigens administered in the absence of adjuvants. Antibodies to CD62P, which blocked CD4+ TEM cell migration into reactive lymph nodes, inhibited DC maturation, T cell priming, and induction of EAE. These results show that TEM cells can behave as endogenous adjuvants and suggest a mechanistic link between lymphocyte traffic in lymph nodes and induction of autoimmunity.

scholarly journals Targeted in-vitro-stimulation reveals highly proliferative multi-virus-specific human central memory T cells as candidates for prophylactic T cell therapy

PLoS ONE ◽  
2019 ◽  
Vol 14 (9) ◽  
pp. e0223258 ◽  
Author(s):  
Benjamin Faist ◽  
Fabian Schlott ◽  
Christian Stemberger ◽  
Kevin M. Dennehy ◽  
Angela Krackhardt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Memory T Cells ◽  
Central Memory ◽  
T Cell Therapy ◽  
Central Memory T Cells

Naïve T Cell-Derived CTL Recognize Atypical Epitopes of CMVpp65 with Higher Avidity Than CMV-Seropositive Donor-Derived CTL – a Basis for Treatment of Post-Transplant Viral Infection by Adoptive Transfer of T Cells From Virus-naïve Donors

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3002-3002
Author(s):  
Patrick J Hanley ◽  
J. Joseph Melenhorst ◽  
Phillip Scheinberg ◽  
Gail J Demmler-Harrison ◽  
Daniele Lilleri ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Transfer ◽  
Memory T Cells ◽  
Conflicts Of Interest ◽  
Target Cells ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Infected Cells

Abstract Abstract 3002 Adoptive transfer of CMV-specific T cells derived from adult CMV-seropositive (CMVpos) donors can effectively restore antiviral immunity after stem cell transplantation. However due to the absence of CMV antigen-specific memory T cells in cord blood (CB) and adult CMV-seronegative (CMVneg) donors, different culture systems are required to generate virus-specific T cells for adoptive transfer. With a novel protocol we have generated CMVpp65-specific T cells from CB and found that 15/15 CB T cell lines recognized atypical epitopes of pp65. We then explored the generation of CMV-specific CTL from CMVneg donors using a GMP-compliant methodology and studied the epitopes recognized. CD45RA+ naive T cells were selected from the peripheral blood of CMVneg donors and stimulated with pp65-Pepmix-pulsed dendritic cells with supplemented with IL-7, IL-12, and IL-15. For subsequent stimulations T cells were stimulated with pp65-Pepmix-pulsed EBV-LCL and IL-15 or IL-2. CMVpp65-specific T cells (CMV-CTL) expanded from 8 of 11 CMVneg donors were primarily CD8+ T cells (mean 71%). Naïve donor CMV-CTL secreted IFN- γ in response to pp65 peptides (mean 224; range: 38–611 SFC/1×105 cells) compared to irrelevant peptides (mean 12;Range 3–37) as measured in Elispot assays and lysed pp65-pulsed target cells (mean :48; range :15–70%) but not negative controls (mean 22; range 4–40%). These CMV-CTL derived from naive (but not memory) T cells recognized only novel and atypical pp65 epitopes (such as the HLA-A2-restricted epitopes LQTGIHVRV and MLNIPSINV) but not the typical HLA-A2-restricted epitope NLVPMVATV as confirmed by ELISPOT and multimer analysis. These results are similar to CB-derived CTL. Analysis of the avidity of naïve donor CTL specific for the atypical CMV epitopes revealed that the 1/2 maximum effective concentration was similar (mean: 600 pM) to CMVpos CTL recognizing typical epitopes (mean: 300 pM), and more avid than CMVpos CTL recognizing atypical epitopes (mean: 4 nM), highlighting the difference between naïve-derived and memory-derived CTL. TCR sequencing performed on T cells specific for typical (CMVpos) and atypical (CMVpos, CMVneg, and CB) epitopes revealed that CMVpos donor CMV-CTL recognizing typical epitopes were markedly more oligoclonal than CTL recognizing the atypical epitopes derived from CB, CMVpos, or CMVneg donors. To address the concern that atypical epitopes might not be naturally presented by CMV-infected cells and therefore not recognized by in vitro generated CTL, we tested whether CMV CTL (from CB, CMVpos, CMVneg) generated using CMV AD169-infected fibroblasts or CMV VR1814-infected DCs would recognize the same epitopes. As before, CMVpos CMV CTL recognized typical epitopes of pp65 while CB and CMVneg CMV CTL recognized only atypical epitopes, suggesting that the epitopes are naturally processed and presented by APCs, and that the atypical epitopes observed are not an artifact of using exogenous antigens like the pp65 Pepmix. Thus, despite their unusual repertoire, T cells derived from CB or CMVneg donors are likely to control CMV infection. These results reveal major differences in the naïve and memory CMV specific T cell repertoire that merits further exploration. Nevertheless, we demonstrated that atypical epitopes are naturally presented by CMV infected cells and we are now evaluating the clinical efficacy of these CTL in recipients of CBT. These studies should determine if naive T cells primed in vitro are able to persist and establish memory and virus protection in vivo. Disclosures: No relevant conflicts of interest to declare.

Activation of T and NK Cells Following Lenalidomide Therapy in Patients with Follicular Lymphoma.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2766-2766
Author(s):  
Seema Rawal ◽  
Nathan Fowler ◽  
Min Zhang ◽  
Zhiqiang Wang ◽  
Tariq Muzzafar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Nk Cells ◽  
Research Funding ◽  
Memory T Cells ◽  
T Cell Subsets ◽  
Central Memory T Cells

Abstract Abstract 2766 Background: Lenalidomide plus rituximab therapy is a highly effective and well-tolerated therapy in patients (pts) with follicular lymphoma (FL). In a Phase II trial, this combination induced a complete remission rate of 87% in pts with advanced stage untreated FL (Fowler et al, Ann Oncol, 2011; 22; suppl 4:137). A randomized Phase III trial was recently initiated to compare this combination with current standard of care therapies in pts with FL. Although lenalidomide is known to be an immunomodulatory drug with effects on a variety of immune cells in vitro, its effects have not been well studied in vivo in humans. Understanding the in vivo effects of lenalidomide could lead to novel combination strategies to enhance the efficacy and improve clinical outcome in FL and other malignancies. Methods: Pts received lenalidomide 20 mg/day on days 1–21 of each 28-day cycle and rituximab was given at 375 mg/m2on day 1 of each cycle. Peripheral blood mononuclear cells (PBMC) were phenotyped by multiparametric flow cytometry at baseline, on cycle 2 day 15 (C2D15), and at the end of cycle 6. In addition, peripheral blood (PB) samples were collected in PAXgene Blood RNA tubes at baseline and on C2D15 for whole genome gene expression profiling (GEP). Results: Immunophenotyping of baseline and end of cycle 6 PBMC (n=17) showed that the percentages and absolute numbers of CD3+, CD4+, CD8+, TCRgd, and Foxp3+ regulatory T cells; and NK, NKT, and myeloid dendritic cells were not significantly different between the two time points. However, a significant increase in CD4+CD45RO+ (p<0.01) and CD8+CD45RO+ (p=0.04) memory T cells was observed post-therapy. Further characterization of CD4+ T cells showed a significant increase in central memory T cells (p<0.001) and a decrease in naïve (p<0.01) and terminally differentiated (p<0.01) T cells, but no change in effector memory T cells. The increase in CD8+ central memory T cells was marginally significant (p=0.06). Plasmacytoid dendritic cells (PDC) were also significantly increased (p=0.02). In contrast, no such changes in T cell subsets or PDC were observed in FL pts (n=9) treated with 6 cycles of R-CHOP chemotherapy that received equal number of rituximab doses and analyzed at similar time points (baseline and end of cycle 6). To understand lenalidomide-induced changes on a molecular level, we compared GEP data at C2D15 vs. baseline for 7 pairs of PB samples. The paired significance analysis of microarrays method, based on Student's t test, identified 1,748 differentially expressed genes (DEG; 713 up, 1035 down), without a fold-change threshold, in C2D15 samples vs. baseline. Results were influenced by rituximab-induced depletion of B cells in C2D15 samples, but there were many changes that suggested altered PBMC physiology. Noteworthy up-regulated genes (>1.5 fold) included genes associated with T and NK cell activation including BATF, CCR2, CD1B, CD2, CD160, CTLA4, CXCR3, ICOS, and LAG3; and CD163 and CD209, phagocytic receptors expressed on monocytes/macrophages. Down-regulated genes (>1.5 fold) included CXCR5, which mediates B cell migration into follicles; and IL1B and TNFSF13B (BAFF), which are produced by activated macrophages and induce B cell proliferation. Gene set enrichment analysis of all GEP results, and Ingenuity Pathway Analysis of DEGs, indicated up regulation of multiple pathways and processes including ribosomal and mitochondrial components involved in translation and oxidative phosphorylation, CTLA4 signaling in cytotoxic T cells, and differentiation and signaling by ICOS and CD28 in T helper cells. We confirmed up regulation of CTLA4, ICOS, and LAG3 at the protein level in C2D15 PBMC by flow cytometry. Furthermore, treatment of PBMC derived from untreated FL pts with lenalidomide in vitro resulted in up regulation of these molecules in T and/or NK cells consistent with our in vivo results. Conclusions: In FL pts, lenalidomide induced multiple changes in the immune system including increases in PDC and memory T cell subsets, activation of T and NK cells, and down-regulation of certain genes mediating B cell migration and proliferation. These results provide insights into the mechanism of action of lenalidomide and suggest that it can be combined with other immunostimulatory agents such as therapeutic vaccines, adoptive T cell therapy strategies, and immune checkpoint inhibitors to further enhance its efficacy in FL and other malignancies. Disclosures: Fowler: Celgene: Research Funding. Heise:Celgene Corporation: Employment, Equity Ownership. Lacerte:Celgene: Honoraria. Samaniego:Celgene: Research Funding. Neelapu:Celgene Corporation: Research Funding.

scholarly journals Phenotypic and functional alteration of CD4+ T cells after antigen stimulation. Resolution of two populations of memory T cells that both secrete interleukin 4.

1989 ◽  
Vol 169 (6) ◽  
pp. 2245-2250 ◽  
Author(s):  
K Hayakawa ◽  
R R Hardy
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
T Cell Subsets ◽  
Interleukin 4 ◽  
Permanent Loss ◽  
Two Populations ◽  
Functional Alteration

Phenotypic and functional alteration of murine CD4+ T cells after antigenic stimulation was studied using two anti-T cell mAbs recently described that define four distinct T cell subsets. Activation of T cells resulted in the permanent loss of 3G11 expression. However, two phenotypically distinct memory T cell populations were established depending on the system used; whereas those for anti-KLH antibody response were enriched in the fraction expression 6C10 (Fr. III), memory T cells for the allogeneic MLR lacked such expression (Fr. IV). Furthermore, successive stimulation with antigen in vitro resulted in secretion of IL-4 without detectable IL-2. This alteration of phenotype and interleukin secretion was also demonstrable when starting with 3G11+6C10- cells (Fr. I), the fraction that secretes IL-2 exclusively upon activation.

Accessory Signals in T-T Cell Interactions Between Antigen- and Alloantigen-Specific, Human Memory T Cells Generated in Vitro

1990 ◽  
Vol 31 (6) ◽  
pp. 717-728 ◽  
Author(s):  
N. ODUM ◽  
L. P. RYDER ◽  
J. GEORGSEN ◽  
B. K. JAKOBSEN ◽  
C. GEISLER ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Human Memory ◽  
Cell Interactions

scholarly journals 778 Modulating tumor microenvironment with arginase-1 specific T cells

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A813-A813
Author(s):  
Evelina Martinenaite ◽  
Mia Aaboe Jørgensen ◽  
Rasmus Erik Johansson Mortensen ◽  
Shamaila Munir Ahmad ◽  
Stine Emilie Weis-Banke ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Memory T Cells ◽  
Ethics Committee ◽  
Mouse Tumor ◽  
Immune Modulators ◽  
Arginase 1 ◽  
Mouse Tumor Models

BackgroundIO112 is an immune modulatory cancer therapy under preclinical development to target arginase-1-expressing tumor cells and immune inhibitory myeloid cells, such as myeloid derived suppressor cells (MDSCs), and tumor associated macrophages (TAMs). Arginase-1 acts as a metabolic immune regulator at the tumor site by reducing availability of L-arginine to the infiltrating immune cells thus reducing T cell functionality and proliferation. Previously, we demonstrated that IO112 triggers activation of spontaneous CD4+ and CD8+ T-cell responses against arginase-1, found in both cancer patients and healthy individuals.1 These T cells are present in the memory T cell compartment, and are activated in arginase-1 inducing conditions, such as presence of TH2 cytokines IL-4 or IL-13 in vitro.2 3 In this study we aimed to explore the role of arginase-1-specific T cells as immune modulators in immune homeostasis and tumor microenvironment for the development of IO112 immunomodulatory therapy.MethodsHuman arginase-1-specific T cells were isolated and expanded for functional characterization of reactivity against arginase-1 expressing target cells as well as subsequent phenotyping of the targeted arginase-1 positive cells. Syngeneic C57BL/6 mouse tumor models were used to assess the therapeutic efficacy of IO112.ResultsWe show that arginase-1-specific memory T cells specifically recognize arginase-1 expressing cells, such as mRNA transfected autologous dendritic cells (DCs) and B cells as well as M2 polarized macrophages in vitro. In addition, activated arginase-1-specific T cells produce pro-inflammatory cytokines IFNγ and TNFα. Secretion of TH1 cytokines by these T cells suggests that they may act as potent immune modulators in the tumor microenvironment, since many arginase-1 expressing myeloid cells are not terminally differentiated and they can be re-polarized to an immunostimulatory, M1-like phenotype. We also observed that targeting of M2-polarized arginase-1 expressing monocytic leukemia cell line THP-1 with arginase-1-specific CD4+ T cells induces upregulation of PD-L1 on the THP-1 cells. Furthermore, we demonstrate anti-tumor activity of IO112 in syngeneic mouse tumor models (B16 and MC38), both as monotherapy and in combination with anti-PD-1 treatment. The therapeutic effect was associated with increased immune infiltration in the IO112-treated mice compared to the control.ConclusionsWe demonstrate that arginase-1 specific T cells can influence the polarization of arginase-1-expressing immune cells. Our study provides evidence that IO112 immune therapy against arginase-1 is an attractive way of modulating the immune suppressive tumor microenvironment for therapeutic benefit. With this rationale, we are currently undertaking Investigational New Drug (IND) application enabling studies to explore this approach in a clinical setting.ReferencesMartinenaite E, Mortensen REJ, Hansen M, Holmström MO, Ahmad SM, Jørgensen NGD, Met Ö, Donia M, Svane IM, Andersen MH. Frequent adaptive immune responses against arginase-1. Oncoimmunology 2018;7(3):e1404215.Martinenaite E, Ahmad SM, Svane IM, Andersen MH. Peripheral memory T cells specific for Arginase-1. Cell Mol Immunol 2019;16(8):718–719.Martinenaite E, Ahmad SM, Bendtsen SK, Jørgensen MA, Weis-Banke SE, Svane IM, Andersen MH. Arginase-1-based vaccination against the tumor microenvironment: the identification of an optimal T-cell epitope. Cancer Immunol Immunother 2019;68(11):1901–1907.Ethics ApprovalThis study was approved by the Scientific Ethics Committee for The Capital Region of Denmark and Danish Ethics Committee on experimental animal welfare.

Akt Signalling Inhibition Promotes The Ex Vivo generation Of Minor Histocompatibility Antigen-Specific CD8+ Memory Stem T Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3269-3269
Author(s):  
Anniek B. van der Waart ◽  
Noortje van der Weem ◽  
Luca Gattinoni ◽  
Nicolaas PM Schaap ◽  
Robbert van der Voort ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Ex Vivo ◽  
Akt Inhibitor ◽  
Memory Subset

Abstract Allogeneic hematopoietic stem cell transplantation (allo-SCT) followed by donor lymphocyte infusion (DLI) is a potential curative treatment for patients suffering from a hematological malignancy. Efficacy is attributed to the graft-versus-tumor (GVT) response, during which engrafted donor T cells become activated by recipient minor histocompatibility antigens (MiHA) presented on dendritic cells (DC). Subsequently, these activated T cells expand, acquire effector functions and kill MiHA-positive tumor cells. However, persistence and recurrence of malignant disease is often observed, indicating that insufficient GVT immunity is induced. This imperfect alloreactive response is probably due to insufficient numbers of MiHA-specific effector T cells and/or defective antigen-presentation and costimulation. Therefore, adoptive transfer of potent ex vivo-generated MiHA-specific T cells, restricted to the hematopoietic system, would boost the GVT-effect without increasing the risk for GVHD. Although successful in vitro induction of MiHA-specific CD8+ T cells from naive precursors has been reported, the resulting antigen-experienced T cell population consist of fully differentiated effector-memory T cells (TEM). Over the past years it has been described that this T cell subset is not the most potent memory subset in anti-tumor responses in vivo following T cell transfer. In this regard, the less-differentiated memory subset called stem cell memory T cells (TSCM) with superior in vivo expansion, self-renewal capacity and plasticity to differentiate in potent effectors would generate a stronger GVT response. In this study, we aimed to investigate the in vivo availability and ex vivo generation of TSCM-like MiHA-specific T cells as additive treatment option for allo-SCT patients. First, we investigated whether in allo-SCT patients MiHA-specific T cells could be detected with a TSCM phenotype defined by the expression of CD45RO, CCR7, CD27 and CD95. Though TSCM cells could be clearly detected within CMV-specific CD8+ T cells in allo-SCT patients, similar to healthy controls, no MiHA-specific TSCM cells could be detected. This emphasises the need for more potent adoptive MiHA-specific T cell therapy following allo-SCT. Therefore, we next explored the possibility of generating TSCM-like CD8+ T cells by interfering with the Akt signalling pathway. Emerging findings indicate that the differentiation program of CD8+ T cells is dictated by the strength and duration of AKT activity. Therefore, we explored whether the pharmacological inhibition of this signaling pathway could results in the generation of TSCM-like CD8+ T cells. We stimulated CCR7+CD45RA+ naive CD8+ T cells with CD3/CD28 beads plus IL-2, IL-7 and/or IL-15 in the presence an Akt inhibitor. Interestingly, CD8+ T cells in these Akt-cultures were inhibited in their differentiation stage, expressing higher levels of CD45RA and CCR7 compared to controls. In addition, expression of CD95, IL2Rβ, and IL7Rα was also elevated confirming the TSCM-like phenotype. Although proliferation of the Akt-inhibited CD8+ T cells was decreased as shown by less PBSE dilution, expansion could be significantly preserved. Next, we investigated whether the established culture conditions could be used to generate MiHA-specific TSCM-like cells. Therefore, CD8+ T cells from MiHA-negative donors were primed using autologous MiHA peptide-loaded moDCs in the presence of the Akt-inhibitor. Interestingly, MiHA-specific T cell priming could be induced, consisting of mainly TCM and TSCM-like cells compared to almost entirely TEM cells in the control setting. Akt-inhibited MiHA-specific T cells showed higher expression of CCR7, CD45RA, CD62L, CD28, CD95, and IL7Rα. Importantly, for the Akt-inhibited MiHA-specific T cells, proliferation was reserved, resulting in robust proliferation capacity during restimulation after removal of the Akt-inhibitor. The resulting TEFF cells were highly functional, showing capacity to degranulate and produce IFNγ upon peptide restimulation. In conclusion, by inhibiting the Akt-pathway, in vitro CD8+ T cell differentiation can be reduced. Therefore, Akt signalling inhibition can be exploited for generating TSCM-like MiHA-specific T cells in adoptive immunotherapy after allo-SCT. Disclosures: No relevant conflicts of interest to declare.

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