4-1BB Is Superior to CD28 Costimulation for Generating CD8+ Cytotoxic Lymphocytes for Adoptive Immunotherapy

Zhang, Hua; Snyder, Kristen; Suhoski, Megan M.; Maus, Marcela V.; Kapoor, Veena; June, Carl H.; Mackall, Crystal L.

doi:10.4049/jimmunol.179.7.4910

Cited by 188 publications

(164 citation statements)

References 54 publications

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“…Our aAPC-induced cultures demonstrated that signals through the T cell receptor and CD28 alone were sufficient for successful expansion of competent polyfunctional antigen-specific CD8 + T cells. The beneficial role of additional or alternate costimulatory signals for successful T cell expansion cannot be excluded (46)(47)(48), and the differential need for such signals could explain the lesser expansion of H576-specific compared to M1-specific cells. Although our initial experiments were focused on signal 1 and 2, the modular aspect of the aAPC system permits the addition of other stimulatory or inhibitory components that can be used to study the regulation of CD8 + T cell differentiation.…”

Section: ) Expansion Of Multifunctional Cd8 + T Cells With Modcs Imentioning

confidence: 99%

Dynamic regulation of functionally distinct virus-specific T cells

Ndhlovu

Oelke

Schneck

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The functional capacities of CD8 + T cells important for virus clearance are influenced by interactions with antigen presenting cells (APCs) and CD4 + T cells during initial selection, subsequent expansion, and development of memory. Recently, investigators have shown that polyfunctional T cells correlate best with long-term protection, however, it is still unknown how to stimulate T cells to achieve these responses. To study this, we examined the phenotypes and functions of CD8 + T cells specific for two different virus antigens stimulated ex vivo using either autologous monocytederived dendritic cells (moDCs) or HLA-A2-Ig-based artificial APCs (aAPCs). Although similar numbers of influenza virus and measles virus tetramer-positive cells were generated by stimulation with peptide-loaded moDCs and aAPCs, T cell function, assessed by expression of IL-2, IFN-γ, TNF-α, MIP1β, and CD107a, showed that aAPC-generated CD8 + T cells were multifunctional, whereas moDC-generated cells were mostly monofunctional. aAPC-generated cells also produced more of each cytokine per cell than CD8 + T cells generated with moDCs. These phenotypes were not fixed, as changing the culture conditions of expanding T cells from aAPCs to moDCs, and moDCs to aAPCs, reversed the phenotypes. We conclude that CD8 + T cells are heterogeneous in their functionality and that this is dependent, in a dynamic way, on the stimulating APC. These studies will lead to understanding the factors that influence induction of optimal CD8 + T cell function.antigen presenting cells | CD8 T cells | viral immunity | multifunctional T cells

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Section: ) Expansion Of Multifunctional Cd8 + T Cells With Modcs Imentioning

confidence: 99%

Dynamic regulation of functionally distinct virus-specific T cells

Ndhlovu

Oelke

Schneck

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…To determine whether the decreased expression of OX40 observed in the patient had an effect on the survival or proliferation kinetics of CD4+ T cells, K562-based artificial antigen presenting cells (aAPCs) expressing OX40L or 4-1BBL were used to provide costimulation to patient and donor control cells. The aAPC system employed has been previously shown to support anti-CD3 mediated polyclonal T cell expansion and survival in vitro [29,33]. Using this system, we observed enhanced proliferation of the patient's CD4+ T cells when compared to normal controls ( Figure 3A).…”

Section: Cd4+ T Cell Proliferation and Viabilitymentioning

confidence: 78%

Monosomy 1p36 uncovers a role for OX40 in survival of activated CD4+ T cells

Suhoski¹,

Perez²,

Heltzer³

et al. 2008

Clinical Immunology

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Monosomy 1p36 is a subtelomeric deletion syndrome associated with congenital anomalies presumably due to haploinsufficiency of multiple genes. Although immunodeficiency has not been reported, genes encoding costimulatory molecules of the TNF receptor superfamily (TNFRSF) are within 1p36 and may be affected. In one patient with monosomy 1p36, comparative genome hybridization and fluorescence in-situ hybridization confirmed that TNFRSF member OX40 was included within the subtelomeric deletion. T cells from this patient had decreased OX40 expression after stimulation. Specific, ex vivo T cell activation through OX40 revealed enhanced proliferation, and reduced viability of patient CD4 + T cells,providing evidence for the association of monosomy 1p36 with reduced OX40 expression, and decreased OX40-induced T cell survival. These results support a role for OX40 in human immunity, and calls attention to the potential for haploinsufficiency deletions of TNFRSF co-stimulatory molecules in monosomy 1p36.

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“…This might be because of the culture conditions specific to each study. It has been reported that the anti-CD3 and anti-CD28 stimulation as used here preferentially expand CD45RO-cells (55). CD57 is a marker associated with the end-stage T-cell differentiation.…”

Section: Discussionmentioning

confidence: 91%

Predicting Cytotoxic T-cell Age from Multivariate Analysis of Static and Dynamic Biomarkers

Rivet

Hill

et al. 2011

Molecular & Cellular Proteomics

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Adoptive T-cell transfer therapy relies upon in vitro expansion of autologous cytotoxic T cells that are capable of tumor recognition. The success of this cell-based therapy depends on the specificity and responsiveness of the T cell clones before transfer. During ex vivo expansion, CD8؉ T cells present signs of replicative senescence and loss of function. The transfer of nonresponsive senescent T cells is a major bottleneck for the success of adoptive T-cell transfer therapy. Quantitative methods for assessing cellular age and responsiveness will facilitate the development of appropriate cell expansion and selection protocols. Although several biomarkers of lymphocyte senescence have been identified, these proteins in isolation are not sufficient to determine the age-dependent responsiveness of T cells. We have developed a multivariate model capable of extracting combinations of markers that are the most informative to predict cellular age. To acquire signaling information with high temporal resolution, we designed a microfluidic chip enabling parallel lysis and fixation of stimulated cell samples on-chip. The acquisition of 25 static biomarkers and 48 dynamic signaling measurements at different days in culture, integrating single-cell and population based information, allowed the multivariate regression model to accurately predict CD8؉ T-cell age. From surface marker expression and early phosphorylation events following T-cell receptor stimulation, the model successfully predicts days in culture and number of population doublings with R 2 ‫؍‬ 0.91 and 0.98, respectively. Furthermore, we found that impairment of early signaling events following T cell receptor stimulation because of long term culture allows prediction of costimulatory molecules CD28 and CD27 expression levels and the number of population divisions in culture from a limited subset of signaling proteins. The multivariate analysis highlights the information content of both averaged biomarker values and heterogeneity metrics for prediction of cellular age within a T cell population.

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4-1BB Is Superior to CD28 Costimulation for Generating CD8+ Cytotoxic Lymphocytes for Adoptive Immunotherapy

Cited by 188 publications

References 54 publications

Dynamic regulation of functionally distinct virus-specific T cells

Dynamic regulation of functionally distinct virus-specific T cells

Monosomy 1p36 uncovers a role for OX40 in survival of activated CD4+ T cells

Predicting Cytotoxic T-cell Age from Multivariate Analysis of Static and Dynamic Biomarkers

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