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Generation of highly proliferative rejuvenated cytotoxic T cell clones through pluripotency reprogramming for adoptive immunotherapy

ABSTRACT: Adoptive immunotherapy has emerged as a powerful approach to cure cancer and chronic infections. Currently, the generation of a massive number of T cells that provide long-lasting immunity is challenged by exhaustion and differentiation-associated senescence, which inevitably arise during in vitro cloning and expansion. To circumvent these problems, several studies have proposed an induced pluripotent stem cell (iPSC)-mediated rejuvenation strategy to revitalize the exhausted/senescent T-cell clones. Because iPSC-derived cytotoxic T lymphocytes (iPSC-CTLs) generated via commonly used monolayer systems have unfavorable innate-like features such as aberrant natural killer (NK) activity and limited replication potential, we modified the redifferentiation culture to generate CD8ab+CD5+CCR7+CD45RA+CD56- adaptive iPSC-CTLs. The modified iPSC-CTLs exhibited early memory phenotype, including high replicative capacity and the ability to give rise to potent effector cells. In expansion culture with an optimized cytokine cocktail, iPSC-CTLs proliferated more than 10^15-fold in a feeder-free condition. Our redifferentiation and expansion package of early memory iPSC-CTLs could supply memory and effector T cells for both autologous and allogeneic immunotherapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE173377 | GEO | 2021/04/27

REPOSITORIES: GEO

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Single-cell transcriptome and TCR analysis of human Cytomegalovirus (hCMV)-specific T cell memory reveals effector and pre-effectors of CD8+ and CD4+ cytotoxic T cells

Project description:The latent human Cytomegalovirus (hCMV) infection can pose a serious threat of reactivation and disease occurrence in immune-compromised individuals, as well as burdens the immune system in immune-competent individuals. Though, T cells are at the core of the protective immune response to hCMV infection, a detailed characterization of different T cell subsets involved in protection against the hCMV infection is lacking. Here we analyzed the single-cell transcriptomes and the single-cell T cell antigen receptor (TCR) repertoires of over 8000 hCMV-reactive peripheral T cells isolated from different memory compartments. The hCMV-reactive T cells were highly heterogeneous and consisted of different developmental memory and functional T cell subsets such as, the long-term memory precursors and effectors, T helper-17, T regulatory cells (TREGs) and cytotoxic T lymphocytes (CTLs). The hCMV-antigen specific TREGs were enriched for molecules linked to their suppressive function and interferon response genes. The CTLs were of two types, the pre-effector and effector like. Of particular interest was the mixture of both CD4-CTLs and CD8-CTLs in both the pre-effector and effector cytotoxic clusters, suggesting that both CD4-CTLs and CD8-CTLs share transcriptomic signatures. The huge TCR clonal expansion of both the cytotoxic clusters imply their predominant role in protective immune response to CMV. Further the clonotype sharing between the CTL clusters and the long-term memory clusters, indicate potential progenitors of CD4-CTLs. Together our study has identified many subsets of hCMV-specific memory T cells that may have implication in better understanding the hCMV-specific T cell immunity to design vaccination strategies and therapeutics.

2024-03-20 | GSE235604 | GEO

A microRNA-directed program of cytotoxic CD8+ T cell differentiation

Project description:Acquisition of effector properties is a key step in the generation of cytotoxic T lymphocytes (CTLs). Here we show that inflammatory signals regulate Dicer expression in CTL, and that deletion or depletion of Dicer in mouse or human activated CD8+ T cells causes upregulation of perforin, granzyme and effector cytokines. Genome-wide analysis of miRNA changes induced by exposure of differentiating CTLs to IL-2 and inflammatory signals identifies miR-139 and miR-150 as components of a miRNA network that controls perforin, eomesodermin (Eomes) and IL-2Ra expression in differentiating CTLs and whose activity is modulated by IL-2, inflammation and antigenic stimulation. Overall our data show that strong IL-2R and inflammatory signals act through Dicer and miRNAs to control the cytolytic program and other aspects of effector CTL differentiation. Comparison of control and Dicer knock-out CTLs differentiated in vitro; Comparison of wild type CTLs differentiated in vitro with or without inflammatory stimuli; Comparison of effector and memory precursor CTLs isolated from mice infected with LCMV-Armstrong

2013-12-02 | E-GEOD-51393 | biostudies-arrayexpress

Gene expression profile of regenerated CD8αα T cells and CD8αβ T cells from LMP2 T-iPSCs

Project description:Whereas cytotoxic T lymphocytes (CTLs) represent the most promising therapeutic avenue in cancer immunotherapy, adaptive transfer of antigen-specific CTLs has faced difficulty in efficient expansion of CTLs from patients in ex vivo culture. To solve this issue, several groups have proposed that the induced pluripotent stem cell (iPSC) technology can be applied for the expansion of antigen-specific CTLs: when iPSCs are produced from antigen-specific CTLs and CTLs are induced from these iPSCs, all regenerated CTLs express the same TCR as original CTLs. However, in these previous studies, one critical issue remains to be solved. With current methods, the regenerated CTLs are mostly of the CD8αα+ innate type and have less antigen-specific cytotoxic activity than primary CTLs. Here we report that, by stimulating purified iPSC-derived CD4/CD8 double positive (DP) cells with anti-CD3 antibody, T cells expressing CD8αβ were generated and they had cytotoxic activity comparable to primary CTLs.

2016-11-15 | GSE81975 | GEO

Gene expression profiles of human CD8+ T cells: IL-12 and IFN-a polarized in vitro stimulated and ex vivo sorted CCR7hi and CXCR3hi populations

Project description:CD8+ cytotoxic T lymphocytes (CTLs) play a major role in defense against intracellular pathogens, and their functions are specified by antigen recognition and innate cytokines. While effector CTLs eliminate the infection, a small population of memory cells are retained that yields more rapid and robust response upon re-infection. Antigen presenting cells secrete an array of innate cytokines including IL-12 and IFN-α after recognition of pathogens. Both IL-12 and IFN-α have been shown to act as the third signal regulating the development of CTLs. We have shown that these two cytokines have a non-redundant effect in generation of human effector CTL. IL-12 alone is sufficient for effector CTL genesis marked by IFN-γ and TNF-α production, as well as increased cytolytic activity. Even in the presence of IFN-α, IL-12 programs CTLs that express the chemokine receptor CXCR3 and effector cytokines. Using microarray analysis we have investigated how IL-12 and IFN-α differentially regulate the genetic programming pathways that give rise to effector CTLs among multiple human donors. We have also analyzed the gene expression patterns of cells sorted from healthy human peripheral blood that display surface markers of effector memory CTL (designated as ex vivo) samples. 5 healthy human donor samples were used for the in vitro cultures. For each donor the CFSE labeled cells (CD8+CD45RA+) were cultured in the presence of neutralized, IL-12, IFN-a, and IL-12+IFN-a conditions and plate-bound anti-CD3+anti-CD28 for 3.5 days. Total RNA from CFSEhi (Undiv) and CFSElo (Div) sorted cells were used for Illumina Bead Array. 4 healthy human donor samples were used for the ex vivo samples. Total RNA was collected from FACS sorted CD8+CCR7hiCXCR3lo and CD8+CCR7loCXCR3hi cells without any stimulation.

2011-09-29 | E-GEOD-27337 | biostudies-arrayexpress

Super-killer CTLs are generated by single gene deletion of Bach2

Project description:Bach2 codes for a transcriptional regulator exerting major influences on T cell mediated immune regulation. Effector CTLs derived from in vitro activation of murine CD8+ T cells showed increased proliferative and cytolytic capacity in the absence of BACH2. Before activation, BACH2-deficient CD8+ T cells had a higher abundance of memory and reduced abundance of naïve cells compared to wild-type. CTLs derived from central memory T cells were more potently cytotoxic than those derived from naïve T cells, but even within separated subsets, BACH2-deficiency conferred a cytotoxic advantage. Immunofluorescence and electron microscopy revealed larger granules in BACH2-deficient compared to wild-type CTLs, and proteomic analysis showed an increase in granule content, including perforin and granzymes. Thus, the enhanced cytotoxicity observed in effector CTLs lacking BACH2 arises not only from differences in their initial differentiation state but also inherent production of enlarged cytolytic granules. These results demonstrate how a single gene deletion can produce a CTL super-killer.

2022-09-02 | PXD036457 | Pride

Gene expression profiles of human CD8+ T cells: IL-12 and IFN-a polarized in vitro stimulated and ex vivo sorted CCR7hi and CXCR3hi populations

2011-09-30 | GSE27337 | GEO

Transcriptional basis of CD4 T cel help for memory CD8 T cell formation

Project description:CD4+ T-cell help is required for the generation of CD8+ cytotoxic T lymphocyte (CTL) memory. We here reveal how “help” signals delivered during priming impact memory differentiation of CTLs, as informed by genome-wide analyses. “Help” signals promoted the IL-15-dependent maintenance of central memory (TCM) cells. However, they had a much larger impact on the generation of effector memory (TEM) cells and their gene expression program . CD4+ T-cell help created TEM cells that produced Granzyme B and IFNg after antigen-independent recall with IL-12 and IL-18. Furthermore, “helped” memory CTLs expressed the effector program characteristic of “helped” primary CTLs upon recall with MHC class I-restricted antigen only, due to both epigenetic imprinting and sustained mRNA expression of relevant genes . Thus, CD4+ T-cell help delivered during priming creates CD8+ TEM cells with innate and help-independent recall capacities.

2019-10-23 | GSE135141 | GEO

Altered transcriptional profile of Smad4-deficient CTLs during infection with Listeria

Project description:TGFb is a pleiotropic cytokine which can exert its regulatory effects on differentiation of cytotoxic T lymphocytes (CTLs) and alter their cell fate. Canonical TGFb signaling inhibits the formation of KLRG1+ effector cells and circulating memory cells while inducing the formation of resident memory cells. However, SMAD4 functions contradictory to TGFb where it is required for the formation of KLRG1+ effector cells and circulating memroy cells and actively inhibit the formation of resident memory cells. Using, RNA-Sequencing we identified that Smad4 alters the gene expression profile of pathogen-specific CTLs after intranasal infection with Listeria monocytogenes expressing chicken ovalbumin.

2022-10-04 | GSE214599 | GEO

Lysine Demethylase 6b (Kdm6b) is essential for proper generation of effector CD8+ T lymphocytes by inducing chromatin accessibility in effector-associated genes

Project description:The transcriptional and epigenetic regulation of CD8+ T cell differentiation is critical for balancing pathogen eradication and long-term immunity by effector and memory CTLs. Here, we demonstrate that the Lysine Demethylase 6b (Kdm6b) is essential for the proper generation and function of effector CD8+ T cells during acute infection and tumor eradication. We found that cells lacking Kdm6b (either T cell-specific KO or knockdown utilizing shRNA strategies) show an enhanced generation of memory precursor and early effector cells upon acute viral infection in a cell-intrinsic manner. We also demonstrate that Kdm6b is indispensable for proper effector functions and tumor protection, and that memory CD8+ T cells lacking Kdm6b displayed a defective recall response. Mechanistically, we identified that Kdm6b, through induction of chromatin accessibility in key effector-associated gene loci, allows for the proper generation of effector CTLs. Our results pinpoint the essential function of Kdm6b in allowing chromatin accessibility in effector-associated genes, and identify Kdm6b as a potential target for therapeutics in diseases with dysregulated effector responses.

2021-02-25 | GSE161842 | GEO

Foxp3 expression diversifies the metabolic capacity and enhances the efficacy of CD8 T cells in adoptive T cell therapy

Project description:CD4 regulatory T cells overwhelm conventional T cells in the tumor microenvironment (TME) thanks to a Foxp3-driven metabolic program that allows them to use alternate substrate and engage different metabolic pathways. In this study, we proposed to overexpress Foxp3 in CD8 T cells (CTL) and examine how it affected their antitumor properties. We show that Foxp3 overexpressing (Foxp3UP) CTLs proliferated and markedly accumulated in the TME while showing enhanced cytotoxicity and antitumor efficacy but not suppressor activity. Interestingly, tumor-infiltrating Foxp3UP CTLs exhibited a T-cell effector and leukocyte migration genetic signature, and positive enrichment in glycolysis, fatty acid (FA) metabolism and oxidative phosphorylation (OXPHOS) pathways. Intratumoral Foxp3UP CTLs showed an increased expression of Glut1, enhanced glucose and FA uptake and intracellular lipid accumulation. Interestingly, Foxp3UP CTLs compensated for the loss of mitochondrial respiration-driven ATP production by activating aerobic glycolysis. Moreover, in limiting nutrient conditions these cells engaged FA oxidation to drive OXPHOS for their energetic demands. Further, their ability to couple glycolysis and OXPHOS allowed then to sustain proliferation under glucose restriction. Our findings demonstrate a hitherto unknown role of Foxp3 in the adaptation of CTLs to TME that can be used to enhance their efficacy in adoptive T cell therapy

2022-10-15 | GSE206987 | GEO

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