scholarly journals Subsets of Memory Cytotoxic T Lymphocytes Elicited by Vaccination Influence the Efficiency of Secondary Expansion In Vivo

2004 ◽  
Vol 78 (1) ◽  
pp. 206-215 ◽  
Author(s):  
Michael S. Seaman ◽  
Fred W. Peyerl ◽  
Shawn S. Jackson ◽  
Michelle A. Lifton ◽  
Darci A. Gorgone ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Memory T Cells ◽  
Central Memory ◽  
Effector Memory ◽  
Interleukin 12 ◽  
Effector Cells ◽  
Memory Cytotoxic T Lymphocytes

ABSTRACT Vaccine-elicited cytotoxic T lymphocytes (CTL) should be long-lived memory cells that can rapidly expand in number following re-exposure to antigen. The present studies were initiated to analyze the ability of plasmid interleukin-12 (IL-12) to augment CTL responses in mice when delivered during the peak phase of an immune response elicited by a plasmid human immunodeficiency virus type 1 gp120 DNA vaccine. Delivery of plasmid IL-12 on day 10 postimmunization resulted in a robust expansion of gp120-specific CD8+ T cells, as measured by tetramer, gamma interferon ELISPOT, and functional-killing assays. Interestingly, this delayed administration of plasmid IL-12 had no significant effect on antigen-specific CD4+-T-cell and antibody responses. Phenotypic analyses suggested that administration of plasmid IL-12 near the time of the peak CTL response activated and expanded antigen-specific effector cells, preventing their loss through apoptosis. However, this IL-12-augmented population of gp120-specific CD8+ T cells did not efficiently expand following gp120 boost immunization, suggesting that these effector cells would be of little utility in expanding to contain a viral infection. Analyses of the phenotypic profile and anatomic distribution of the plasmid IL-12-augmented CTL population indicated that these lymphocytes were primarily effector memory rather than central memory T cells. These observations suggest that CTL-based vaccines should elicit central memory rather than effector memory T cells and illustrate the importance of monitoring the phenotype and functionality of vaccine-induced, antigen-specific CTL.

A Comparison of Human CMVpp65-Specific Central Memory and Effector Memory CD8 T-Cells When Stimulated in-Vivo with IL-2 or IL-15/IL-15Rα Complex in a Murine Xenograft Model of Adoptive Cell Therapy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4805-4805
Author(s):  
Tzu-Yun Kuo ◽  
Aisha Hasan ◽  
Richard J O'Reilly
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Adoptive Immunotherapy ◽  
Memory T Cells ◽  
Cd8 T Cell ◽  
Central Memory ◽  
Effector Memory ◽  
Cell Clones

Abstract Initial clinical trials of adoptive immunotherapy have shown that the efficacy of adoptively transferred T-cells in man is often limited by the failure of cultured T cells, particularly cloned CD8 T cells, to persist in vivo. These studies demonstrated that the transferred T cells induced only transient responses and that persistence of the transferred T-cell clonotypes correlated with disease regression. A previous study suggested that CMV virus-specific CD8 T cell clones derived from central memory T cells (TCM), but not effector memory T cells (TEM), persisted long-term in non-human primates. On the other hand, another study comparing TCM and TEM derived SIV virus specific CD8 T-cell clones that were adoptively transferred in non-human primates demonstrated limited persistence of both TCM and TEM derived transferred T cells, and failed to show any difference between the two cell types. Because of these conflicting data, we have reexamed the persistence of adoptively transferred viral antigen specific T-cells derived from TCM and TEM population. Accordingly, we developed a NOG mouse model for studying the ability of human CMVpp65-specific T cells derived from central memory and effector memory populations to migrate to and accumulate in human tumor xenografts expressing CMVpp65, to alter the growth of these tumors and to persist in the tumors. This model also allows us to test immunomodulating agents and their ability to enhance targeted T-cell accumulations, antitumor activity and persistence. We analyzed CMVpp65-specific CD8 T cells derived from TCM and TEM precursors in vitro and in vivo. To tract the T-cells in vivo, we transduced membrane-bound Gaussia luciferase into TCM and TEM populations and monitored T cell trafficking by in vivo bioluminescence. Contrary to expectation, our results initially showed no differences between TCM and TEM derived CMVpp65-specific T-cell in mice co-treated with IL-2 in the time to accumulation, ultimate level of accumulation, degree of CMVpp65+ tumor regression or T-cell persistence. However, in mice cotreated with IL-15/IL-15Rα complex, both TCM and TEM exhibited more sustained engraftment and more prolonged accumulation in both the targeted tumor and in the marrow. In mice treated with IL-15/IL-15Rα, TCM and TEM derived T cells showed a similar effector memory phenotype and a similar level of regression of tumor growth. Thus, adoptive transfer of CMVpp65 specific TCM or TEM when combined with IL-15/IL-15Rα complex may support better persistence of antigen-specific T-cells following adoptive immunotherapy. Studies comparing IL-15/IL-15Rα complex with IL-15 alone are in progress. Disclosures No relevant conflicts of interest to declare.

scholarly journals Engraftment of human central memory-derived effector CD8+ T cells in immunodeficient mice

Blood ◽  
2011 ◽  
Vol 117 (6) ◽  
pp. 1888-1898 ◽  
Author(s):  
Xiuli Wang ◽  
Carolina Berger ◽  
ChingLam W. Wong ◽  
Stephen J. Forman ◽  
Stanley R. Riddell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Effector T Cells ◽  
Central Memory ◽  
Model Systems ◽  
Adoptive T Cell Therapy ◽  
Effector Memory ◽  
T Cell Therapy ◽  
Effector Cells

Abstract In clinical trials of adoptive T-cell therapy, the persistence of transferred cells correlates with therapeutic efficacy. However, properties of human T cells that enable their persistence in vivo are poorly understood, and model systems that enable investigation of the fate of human effector T cells (TE) have not been described. Here, we analyzed the engraftment of adoptively transferred human cytomegalovirus pp65-specific CD8+ TE cells derived from purified CD45RO+CD62L+ central memory (TCM) or CD45RO+CD62L− effector memory (TEM) precursors in an immunodeficient mouse model. The engraftment of TCM-derived effector cells (TCM/E) was dependent on human interleukin-15, and superior in magnitude and duration to TEM-derived effector cells (TEM/E). T-cell receptor Vβ analysis of persisting cells demonstrated that CD8+ TCM/E engraftment was polyclonal, suggesting that the ability to engraft is a general feature of TCM/E. CD8+ TEM/E proliferated extensively after transfer but underwent rapid apoptosis. In contrast, TCM/E were less prone to apoptosis and established a persistent reservoir of functional T cells in vivo characterized by higher CD28 expression. These studies predict that human CD8+ effector T cells derived from TCM precursors may be preferred for adoptive therapy based on superior engraftment fitness.

Adoptive Immunotherapy with Memory T Cells.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-25-sci-25 ◽  
Author(s):  
Helen E. Heslop
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Ex Vivo ◽  
Central Memory ◽  
Effector Memory ◽  
Memory Phenotype ◽  
Effector Memory T Cells ◽  
Effector Memory Cells

Clinical adoptive cellular immunotherapy of malignancy and viral infection should transfer T cells that expand in vivo on exposure to antigen and can enter the memory compartment to persist long-term. A number of factors, including cellular phenotype, influence the behavior of the infused line. Primate studies have shown that antigen-specific CD8+ T cell clones only persisted long-term in vivo if they were derived from central memory T cells, but not from effector memory T cells, reacquiring phenotypic and functional properties of memory T cells.1 Other studies have suggested that adoptive transfer of ex vivo-expanded effector memory T cells will have poor survival and clinical efficacy, reporting instead that less differentiated T cells with longer telomeres exhibit longer persistence. These data imply that prolonged ex vivo expansion, required, for example, for T cell cloning, adversely affects subsequent in vivo expansion and survival. However, our trials administering ex vivo-expanded, polyclonal EBV-specific T cell lines demonstrated that expanded effector memory T cells, infused into a lymphodepleted host, can expand massively in vivo, enter the memory compartment, and persist for up to seven years after infusion. Furthermore, in a study infusing trivirus-specific CTLs with effector memory phenotype, we saw expansion of CTLs specific for the latent viruses CMV and EBV. By contrast, adenoviral-specific CTL persisted only in patients who were acutely infected with the agent2 We recently compared non-specifically activated T cells (ATC) with EBV-specific CTLs derived from the same initial peripheral blood collection and expressing distinguishable chimeric GD2-specific chimeric antigen receptors (CARATC and CAR-CTL). In this study, ATCs were cultured for 14 to 21 days. Between 0.9% and 6.1% retained a central memory (CCR7+, CD62L+) phenotype, up to 30% had an effector memory phenotype (CCR7−, CD62L+), and the remainder had a terminally/fully differentiated effector phenotype. By contrast, EBV-CTL were cultured for 30 to 44 days and expressed no CCR7, but up to 50% were CD62L+, and contained cells that were terminally/fully differentiated effectors and effector memory cells. These EBV-CTLs also all had a CD45RO memory phenotype, while about 13% to 60% of ATCs expressed CD45RA, a marker of naïve T cells. Despite these differences in memory subsets, it was the CAR-CTLs that had the clearly greater persistence and could be shown to retain functionality, while CAR-ATC rapidly disappeared from the circulation and could not be recovered. Hence, factors other than phenotype, such as antigenic stimulation and costimulation almost certainly influence cell fate after infusion, and determine whether or not effector memory cells can re-access the central memory pool. Ultimately, strategies that combine selection of optimal phenotype with the provision of antigen stimulation and co-stimulation and a cytokine milieu that favors homeostatic expansion will likely lead to the most effective outcomes following adoptive T cell transfer.

scholarly journals Metabolic radiolabeling and in vivo PET imaging of cytotoxic T lymphocytes to guide combination adoptive cell transfer cancer therapy

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Dehua Lu ◽  
Yanpu Wang ◽  
Ting Zhang ◽  
Feng Wang ◽  
Kui Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Solid Tumors ◽  
Cytotoxic T Lymphocytes ◽  
Pet Imaging ◽  
Stage Migration ◽  
Cell Transfer ◽  
Tumor Infiltration ◽  
Antitumor Effects

Abstract Background Adoptive T cell transfer-based immunotherapy yields unsatisfactory results in the treatment of solid tumors, partially owing to limited tumor infiltration and the immunosuppressive microenvironment in solid tumors. Therefore, strategies for the noninvasive tracking of adoptive T cells are critical for monitoring tumor infiltration and for guiding the development of novel combination therapies. Methods We developed a radiolabeling method for cytotoxic T lymphocytes (CTLs) that comprises metabolically labeling the cell surface glycans with azidosugars and then covalently conjugating them with 64Cu-1,4,7-triazacyclononanetriacetic acid-dibenzo-cyclooctyne (64Cu-NOTA-DBCO) using bioorthogonal chemistry. 64Cu-labeled control-CTLs and ovalbumin-specific CTLs (OVA-CTLs) were tracked using positron emission tomography (PET) in B16-OVA tumor-bearing mice. We also investigated the effects of focal adhesion kinase (FAK) inhibition on the antitumor efficacy of OVA-CTLs using a poly(lactic-co-glycolic) acid (PLGA)-encapsulated nanodrug (PLGA-FAKi). Results CTLs can be stably radiolabeled with 64Cu with a minimal effect on cell viability. PET imaging of 64Cu-OVA-CTLs enables noninvasive mapping of their in vivo behavior. Moreover, 64Cu-OVA-CTLs PET imaging revealed that PLGA-FAKi induced a significant increase in OVA-CTL infiltration into tumors, suggesting the potential for a combined therapy comprising OVA-CTLs and PLGA-FAKi. Further combination therapy studies confirmed that the PLGA-FAKi nanodrug markedly improved the antitumor effects of adoptive OVA-CTLs transfer by multiple mechanisms. Conclusion These findings demonstrated that metabolic radiolabeling followed by PET imaging can be used to sensitively profile the early-stage migration and tumor-targeting efficiency of adoptive T cells in vivo. This strategy presents opportunities for predicting the efficacy of cell-based adoptive therapies and for guiding combination regimens. Graphic Abstract

scholarly journals CD27 Expression Promotes Long-Term Survival of Functional Effector–Memory CD8+Cytotoxic T Lymphocytes in HIV-infected Patients

2004 ◽  
Vol 200 (11) ◽  
pp. 1407-1417 ◽  
Author(s):  
Adrian F. Ochsenbein ◽  
Stanley R. Riddell ◽  
Michele Brown ◽  
Lawrence Corey ◽  
Gabriela M. Baerlocher ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Cd8 T Cells ◽  
Interleukin 2 ◽  
Tumor Necrosis Factor Receptor ◽  
Cell Receptor ◽  
Effector Memory ◽  
Term Survival ◽  
Functional Consequences

Human immunodeficiency virus (HIV)-specific CD8+ T cells persist in high frequencies in HIV-infected patients despite impaired CD4+ T helper response to the virus, but, unlike other differentiated effector cytotoxic T lymphocytes, most continue to express the tumor necrosis factor receptor family member CD27. Because the ligand for CD27 (CD70) is also overexpressed in HIV-infected hosts, we examined the nature of expression and potential functional consequences of CD27 expression on HIV-specific CD8+ T cells. Analysis of CD27+ and CD27− T cells derived from the same HIV-specific clone revealed that retention of CD27 did not interfere with acquisition of effector functions, and that after T cell receptor stimulation, CD27+ cells that concurrently were triggered via CD27 exhibited more resistance to apoptosis, interleukin 2 production, and proliferation than CD27− T cells. After transfer back into an HIV-infected patient, autologous HIV-specific CD27− T cells rapidly disappeared, but CD27+ T cells derived from the same clone persisted at high frequency. Our findings suggest that the CD27–CD70 interaction in HIV infection may provide CD27+ CD8+ T cells with a survival advantage and compensate for limiting or absent CD4+ T help to maintain the CD8 response.

Enhanced Infiltration of Central Memory T Cells to the Lung Tissue during Allergic Lung Inflammation

2021 ◽  
pp. 1-15
Author(s):  
Mashael Alabed ◽  
Asma Sultana Shaik ◽  
Narjes Saheb Sharif-Askari ◽  
Fatemeh Saheb Sharif-Askari ◽  
Shirin Hafezi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lung Tissue ◽  
Lung Inflammation ◽  
Inflammatory Responses ◽  
Memory T Cells ◽  
Central Memory ◽  
Effector Memory ◽  
Differential Distribution ◽  
Allergic Lung Inflammation

Memory T cells play a central role in regulating inflammatory responses during asthma. However, tissue distribution of effector memory (T<sub>EM</sub>) and central memory (T<sub>CM</sub>) T-cell subtypes, their differentiation, and their contribution to the persistence of lung tissue inflammation during asthma are not well understood. Interestingly, an increase in survival and persistence of memory T cells was reported in asthmatic lungs, which may suggest a shift toward the more persistent T<sub>CM</sub> phenotype. In this report, we investigated the differential distribution of memory T-cell subtypes during allergic lung inflammation and the mechanism regulating that. Using an OVA-sensitized asthma mouse model, we observed a significant increase in the frequency of T<sub>CM</sub> cells in inflamed lungs compared to healthy controls. Interestingly, adoptive transfer techniques confirmed substantial infiltration of T<sub>CM</sub> cells to lung tissues during allergic airway inflammation. Expression levels of T<sub>CM</sub> homing receptors, CD34 and GlyCAM-1, were also significantly upregulated in the lung tissues of OVA-sensitized mice, which may facilitate the increased T<sub>CM</sub> infiltration into inflamed lungs. Moreover, a substantial increase in the relative expression of T<sub>CM</sub> profile-associated genes (EOMES, BCL-6, ID3, TCF-7, BCL-2, BIM, and BMI-1) was noted for T<sub>EM</sub> cells during lung inflammation, suggesting a shift for T<sub>EM</sub> into the T<sub>CM</sub> state. To our knowledge, this is the first study to report an increased infiltration of T<sub>CM</sub> cells into inflamed lung tissues and to suggest differentiation of T<sub>EM</sub> to T<sub>CM</sub> cells in these tissues. Therapeutic interference at T<sub>CM</sub> infiltration or differentiations could constitute an alternative treatment approach for lung inflammation.

scholarly journals IL-7 and IL-21 are superior to IL-2 and IL-15 in promoting human T cell–mediated rejection of systemic lymphoma in immunodeficient mice

Blood ◽  
2010 ◽  
Vol 115 (17) ◽  
pp. 3508-3519 ◽  
Author(s):  
John C. Markley ◽  
Michel Sadelain
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Transfer ◽  
Memory T Cells ◽  
Tumor Rejection ◽  
Effector Memory ◽  
Transfer Model ◽  
Human T Cell

Abstract The γc-cytokines are critical regulators of immunity and possess both overlapping and distinctive functions. However, comparative studies of their pleiotropic effects on human T cell–mediated tumor rejection are lacking. In a xenogeneic adoptive transfer model, we have compared the therapeutic potency of CD19-specific human primary T cells that constitutively express interleukin-2 (IL-2), IL-7, IL-15, or IL-21. We demonstrate that each cytokine enhanced the eradication of systemic CD19+ B-cell malignancies in nonobese diabetic/severe combined immunodeficient (NOD/SCID)/γcnull mice with markedly different efficacies and through singularly distinct mechanisms. IL-7– and IL-21–transduced T cells were most efficacious in vivo, although their effector functions were not as enhanced as IL-2– and IL-15–transduced T cells. IL-7 best sustained in vitro T-cell accumulation in response to repeated antigenic stimulation, but did not promote long-term T-cell persistence in vivo. Both IL-15 and IL-21 overexpression supported long-term T-cell persistence in treated mice, however, the memory T cells found 100 days after adoptive transfer were phenotypically dissimilar, resembling central memory and effector memory T cells, respectively. These results support the use of γc-cytokines in cancer immunotherapy, and establish that there exists more than 1 human T-cell memory phenotype associated with long-term tumor immunity.

Safely Improving the in Vivo Survival of Tumor Specific Cytotoxic T Lymphocytes by Co-Transfer of IL7 Receptor Alpha Chain and icaspase9

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3534-3534
Author(s):  
Juan F Vera ◽  
Valentina Hoyos ◽  
Barbara Savoldo ◽  
Concetta Quintarelli ◽  
Greta A Giordano ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Adoptive Transfer ◽  
Fold Increase ◽  
Suicide Gene ◽  
Antigen Specificity ◽  
Anti Tumor Activity

Abstract Providing a proliferative and survival advantage to tumor-specific cytotoxic T lymphocytes (CTLs) remains a challenge in the adoptive therapy of cancer patients. It is now evident that the in vivo expansion of T cells after adoptive transfer is best accomplished in the lymphodepleted host due to the increased production of endogenous IL15 and IL7, which help restore lymphopoiesis. We have found that antigen activated cytotoxic T lymphocytes (CTLs) directed to tumor associated epitopes (for example derived from EBV, or from cancer testis antigens such as PRAME) down regulate a chain of IL7R, a common γ chain cytokine receptor, impairing their capacity to respond to IL7. We hypothesized that despite receptor downregulation, the signal transduction pathway for IL7R would remain intact in the CTLs so that forced expression of IL7Rα would restore IL7 responsiveness and improve in vivo expansion and survival of CTLs. We used EBV-specific CTLs as our model, and showed in vitro that a functional IL-7Ra molecule can be expressed in CTLs using retroviral gene transfer so that the percentage of receptor + cells increased from 2.4%±0.5% to 50%±20. This modification restored the in vitro proliferation of genetically modified CTLs in response to IL7 so that cell numbers increased from 1×106 cells to 0.1×109 (range, 0.6×108 to 0.3×109)] comparable with the effects of IL2 [from 1×106 cells to 0.7×109 (range, 0.7×107 to 1.6×109)] In contrast, control EBV-CTL with IL7 progressively declined in number (p<0.001) These effects were accomplished without alteration of antigen specificity or responsiveness to other common γ chain cytokines, and cell survival remained antigen dependent. In a xenogeneic mouse model, CTLs expressing IL7Ra significantly expanded in vivo in response to EBV-tumor antigen and the administration of IL7. By day 15, both control CTLs and IL7Ra+ CTLs had modestly proliferated in response to IL-2 (2.3 fold, range 1.1–5.1 for control CTLs, and 2.67 fold, range 0.6 to 8.15 for IL7Ra+ CTLs). In contrast, only IL7Ra+ CTLs significantly expanded in the presence of IL7, showing a 6.09 fold increase (range 0.7 to 25.2) compared to mice that received control CTLs and IL7 (0.9 fold, range 0.5–1.7) (p<0.0001). Modified CTLs also provided enhanced anti-tumor activity. SCID mice engrafted i.p with 3×106 tumor cells marked with Firefly luciferase, showed a rapid increase in signal in the absence of CTLs (Fold increase in luminance = 29.8 median, range 4.4 to 103) by day 14 after tumor engraftment. Similar tumor growth was observed in mice receiving IL7Ra+ CTLs without cytokines (luminance increase14.4 fold, range 1 to 90). In contrast, mice receiving IL7Ra+ CTLs and either IL2 or IL7, had a decline in tumor luminance (fold expansion 0.7, range 0.08 to 2.9, and 0.8, range 0.004 to 3.5, respectively p<0.0001). Although growth of the transgenic T cells remained antigen dependent, as a further safety measure, we incorporated an inducible suicide gene based on icaspase9 that can be activated by exposure to a small chemical inducer of dimerization (CID) (AP20187). Incorporation of this suicide gene did not affect the in vitro or in vivo anti-tumor activity of the CTL’s but allowed them to be rapidly eliminated. So that after a single dose of CID (50 nM) the transgenic population were decreased by >98.5% We conclude that forced expression of the IL-7Ra by CTLs can be used to recapitulate the response of these cells to this cytokine and thereby promote their in vivo anti-tumor activity after adoptive transfer either in a lymphodepleted host or after the administration of the recombinant protein.

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