T-cell receptor/CD28-targeted Immunotherapeutics Generate Functional Melanoma- or HIV-specific Responses by Selectively Driving Naïve T-Cell Expansion
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PROVIDER: PRJNA1208525 | ENA |
REPOSITORIES: ENA
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Project description:Adoptive cell transfer (ACT), an increasingly used immunotherapeutic approach for the treatment of cancer and infectious diseases, typically infuses antigen-specific CD8+ T cells obtained after ex vivo stimulation with patient-derived dendritic cells (DC) loaded with defined peptides. However, broader use of this approach is limited by logistical complexity, variability, cost, and inconsistency in cell quality. To overcome these limitations, we developed a dimeric protein scaffold-based antigen-presentation platform, Immuno-STAT (IST), which delivers peptide-specific TCR activation and costimulatory signaling to robustly expand highly functional antigen-specific CD8+ T cells. We demonstrate that delivering TCR and CD28 signals by IST selectively activates and expands highly functional cytotoxic CD8+ T cells from the naïve CD8+ T cell repertoire specific for the melanoma-associated MART-1 antigen and the HIV-associated SL9 antigen. While naïve MART-1-specific CD8+ T cells were expanded by both MART-1-peptide loaded DC and MART-1-specific IST, naïve SL9-specific CD8+ T cells were expanded only by SL9-specific IST and not by SL9-peptide loaded DC. By enabling ex-vivo expansion of naïve antigen-specific T cells without generation of autologous DC, IST may overcome the practical hurdles limiting the wider use of ACT and expand its use as a therapeutic strategy for both cancer and infectious disease.
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Project description:Profiling of Naïve (CD45RA+CD28+), EM (CD45RA-CD28-) and TEMRA (CD45RA+CD28-) CD8+ T cells
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Project description:To obtain the differentiated profiling of long noncoding RNA expression between CD8+CD28+ T cell subset and CD8+CD28- T cell subset, we have detecte lncRNA profiling between within-individual T cell subsets to identify differentiated lncRNA profiling in five apperant healthy Chinese nenogenarians who were cytomegalovirus-seropositive carriers. Human peripheral blood monocytes from these apperantly healthy CMV-seropositive nonagenarians was gathered. CD8+CD28+ T cells and CD8+CD28- T cells were further isolated using flow cytometry. Differentiated lncRNA profiling was compared between CD8+CD28+ T cells and CD8+CD28- T cells using lncRNA microarry detection within-individually. 586 lncRNAs were found significantly upregulated while 1113 lncRNAs were found significantly downregulated comparing CD8+CD28+ T cells with CD8+CD28- T cells in these Chinese nonagenarians with CMV seropositivity. Expression of ENST00000446590,NR_121652,NR_045006,ENST00000428936,NR_110375 from this differentiated profiling which were identified as previously domumented ageing-related lncRNAs were quantified in the same RNA samples by real-time PCR, confirming lncRNAs take critical role in regulating T cell immunosenesence in healthy nonagenarian Chinese CMV carriers. Diffentiated lncRNA profiling was in-pair compared between total RNAs isolated from CD8+CD28+ T cells and CD8+CD28- T cells within-individually in Chinese nonagenarian CMV carriers.
2016-10-15 | GSE88767 | GEO
Project description:The RLTPR cytosolic protein has an essential role in CD28 costimulation but its mode of action and importance in human T cells remain elusive. Here, using mass spectrometry we showed that CD28, RLTPR and the CARMA1 cytosolic adaptor physically associate in mouse T cells. Although RLTPR is thought to function as an actin-uncapping protein, this property was dispensable for CD28 costimulation. Our findings underpin the convergent function of RLTPR in T cells and suggest that its scaffolding role predominates during CD28 costimulation.
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Project description:Alternative splicing consists of exons that are selectively either included or excluded from the mature mRNA transcript. Previous studies have demonstrated that ~10-15% of alternatively spliced genes undergo signal-induced changes in isoform abundance in activated primary human CD4+ T cells. In the past, signal-induced alternative splicing changes in T cells have been characterized in the context of CD3 and CD28 activation. CD3 is a component of the T Cell Receptor (TCR) which is responsible for recognizing foreign peptides presented on antigen presenting cells. CD28 enhances various signaling events downstream of the TCR to boost the survival of T cells and is required for full T cell stimulation. The contribution of CD28 signaling to transcriptional changes has been well documented, but the impact on splicing has not been investigated. Here we test the hypothesis that CD28 exerts some of its functional impact through the enhancement of splicing changes in stimulated T cells. We utilized poly(A) RNA-seq and the MAJIQ alternative splicing algorithm to analyze splicing events of human CD4+ T cells stimulated with through CD3 in the presence and absence of co-stimulation with CD28. Consistent with previous studies, we identified approximately 400 and 1,000 significant splicing events induced by CD3/CD28 stimulation at 8 and 48 hours of culture, respectively. Alternative splicing changes induced by CD3 and CD3/CD28 stimuli are highly correlative, however, approximately 23% of alternative splicing changes are further enhanced with additional CD28 costimulation at 8 hours of culture. This enhancement drops to 8% of alternative splicing events by 48 hours. Therefore, we conclude that CD28 costimulation increases the magnitude of splicing during T cell activation, in a manner that is eventually compensated for over time with CD3 stimulation alone.
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Project description:The most recurrently mutated oncogene in T-cell acute lymphoblastic leukemia (T-ALL) is NOTCH1. The core Notch complex consists of an ICN protein, a Maml cofactor, and the DNA binding factor Rbpj. The known direct cofactors of Notch appear to act nonselectively, homogeneously driving Notch gene expression functions. It is unclear whether there are direct cofactors of Notch that act selectively and heterogeneously regulate ICN. We discovered that Zmiz1, a Protein Inhibitor of Activated STAT (PIAS)-like coactivator, directly bound ICN1. ChIP-Seq showed that Zmiz1 selectively co-bound only a subset of Notch-regulated enhancers. This led to hypothesize that Zmiz1 regulates only a subset of Notch1 target genes. To investigate this, we performed RNA-Seq on four 8946 cell linesin which L1601P (activated Notch1) or Zmiz1 were expressed alone or in combination. Zmiz1 induced ~10% of Notch target genes. The Notch target gene that was most strongly induced by Zmiz1 was Myc. Our data suggest that Zmiz1 selectively amplifies a subset of Notch target genes with strong amplification of Myc. RNA-Seq in a murine T-ALL cell line
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Project description:T cells stimulated in the absence of CD28 costimulation are functionally anergic, characterized by reduced glucose metabolism and ability to produce effector cytokines. Surprisingly, previous studies have shown relatively few CD28-specific changes in gene transcription upon costimulation. Using mice expressing mutations in the CD28 cytoplasmic tail, we show a major effect of CD28 costimulation is alternative splicing of numerous genes including the glycolytic enzyme pyruvate kinase (Pkm), which is preferentially spliced from Pkm1 to Pkm2 upon stimulation. PKM2 is dispensable for T cell activation, but necessary for CD8+ T cells to utilize aerobic glycolysis, produce effector cytokines, and provide anti-tumor immunity. Mechanistically, CD28 regulates expression of the Cap-Binding Complex adaptor protein ARS2, which binds Pkm splicing factors and facilitates their interaction with the elongating transcript. Data suggest a major function of CD28 costimulation is control of RNA biogenesis in support of T cell transcriptome remodeling and acquisition of effector function.
2023-09-01 | GSE168824 | GEO
Project description:CD28 region-capture HiC of resting and anti-CD3/CD28-stimuated Jurkat cells
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Project description:This analysis reveals the different gene expression profiles between human melanoma tumor infiltrating lymphocytes subsets CD8+CD28+ and CD8+CD28-. Adoptive cell therapy (ACT) is an effective approach that removes tumor-infiltrating lymphocytes (TILs) from this suppressive tumor microenvironment and expands and activates CD8+ and CD4+ T cells in vitro, differentiating them into potent anti-tumor effector cells that can be re-introduced back into patients. One of the key problems that may limit tumor regression and long-term durable clinical responses in ACT is the persistence of TILs following infusion. Our study has indicated that ex vivo expanded TILs to be hypo-responsive to peptide re-stimulation, manifested in slow entry into cell cycle and increased apoptosis. Phenotypic and functional analysis using a number of different T-cell differentiation markers found that CD28 was markedly down-modulated in post-REP cells, while CD27 and CD57 levels showed no statistically-relevant changes in expression. Here on a global gene expression level, microarray gene chip analysis of sorted CD8+CD28+ and CD8+CD28- post-REP TILs revealed a number of key differences in their gene expression profiles; notably, an increase in KIR family member expression, loss of p53-binding proteins, and lower CD127/IL-7Ra gene expression found in the CD28- population. On top of advancing T cell phenotype, reactivation and memory, this set of data may also provide insight for ACT clinical protocol optimization to improve TIL response in vivo.
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