Effect of costimulation on microRNAs levels in human naïve CD4 T cells
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ABSTRACT:
ORGANISM(S): Mus musculus Rattus norvegicus Human gammaherpesvirus 8 JC polyomavirus Betapolyomavirus macacae Human immunodeficiency virus 1 Murid gammaherpesvirus 4 Homo sapiens Human betaherpesvirus 5 Human alphaherpesvirus 1 Betapolyomavirus hominis human gammaherpesvirus 4 Murid betaherpesvirus 1
PROVIDER: GSE36071 | GEO | 2012/02/25
SECONDARY ACCESSION(S): PRJNA151831
REPOSITORIES: GEO
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Project description:microRNA transcriptional profiling of human naïve CD4 T cells comparing cells that saw no activation, only anti-CD3 or anti-CD3 and anti-CD28 to identify microRNAs specifically upregulated by CD28-mediated costimulation. Three conditions experiment. PBS, anti-CD3, anti-CD3 + anti-CD28 all compared to a reference sample. Biological triplicates, independently extracted and activated.
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Project description:Immune responses depend on a dynamic balance between the opposing activities of conventional (Tconv) and regulatory (Treg) CD4+ T cells. While receptor-targeted approaches have been developed based on their modulation of Tconv cells, Tconv and Treg cells share many costimulatory receptors. We aim to determine key differential signaling events downstream of costimulation to find opportunities for selective manipulation of Tconv or Treg cells. This data set includes the transcriptomes of expanded human Tconv and Treg cells that were treated with anti-CD3, anti-CD3/CD28 or anti-CD3/TNFR2 agonistic mAbs for 24 hours.
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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:Engagement of CD27 during naïve CD8+ T (TN) cell activation is critical for T cell memory generation through poorly understood mechanisms. To examine the effects of CD27 signaling during TN cell activation we designed a synthetic trimeric CD70 ligand. In conjunction with T cell receptor (TCR) stimulation, ligation of CD27 resulted in immediate receptor internalization, recruitment of TRAF2/SHP-1, and modulation of Lck and ERK/AKT signaling in cells receiving concurrent CD28 costimulation. Independent of this modulatory effect on CD28 costimulated T cells, CD27 signaling enhanced ATF2, FOXO1, and FOXP1 transcription factor circuits, which induced T cell memory rather than the effector associated gene programs observed with CD28 costimulation alone. CD27-costimulated T cells engineered with a chimeric antigen receptor (CAR) exhibited improved tumor control. CD27 signaling during TN cell activation modulates activation strength and directs memory T cell properties that may benefit therapeutic T cells engineered with CARs or T cell receptors.
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Project description:A transgenic mouse was generated using a CD2-driven transgene containing the cDNA of Ppp2ca to achieve over-expression of PP2Ac in T cells. Naïve CD4 T cells were isolated and lysed at times 0, 6, and 24 hours after stimulation with anti-CD3 and anti-CD28
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Project description:Regulatory T (Treg) cells can facilitate transplant tolerance and attenuate autoimmune- and inflammatory diseases. Therefore, it is clinically relevant to stimulate Treg cell expansion and function in vivo and to create therapeutic Treg cell products in vitro. We report that TNF receptor 2 (TNFR2) is a unique costimulus for naïve, thymus-derived (t)Treg cells from human blood that promotes their differentiation into non-lymphoid tissue (NLT)-resident effector Treg cells, without Th-like polarization. In contrast, CD28 costimulation maintains a lymphoid tissue (LT)-resident Treg cell phenotype. We base this conclusion on transcriptome and proteome analysis of TNFR2- and CD28-costimulated CD4+ Treg cells and conventional T (Tconv) cells, followed by bioinformatic comparison with published transcriptomic Treg cell signatures from NLT and LT in health and disease, including autoimmunity and cancer. These analyses illuminate that TNFR2 costimulation promotes Treg cell capacity for survival, migration, immunosuppression and tissue regeneration. Functional studies confirmed improved migratory ability of TNFR2-costimulated tTreg cells. Flow cytometry validated the presence of the TNFR2-driven Treg cell signature in effector/memory Treg cells from the human placenta as opposed to blood. Thus, TNFR2 can be exploited as driver of NLT-resident Treg cell differentiation for adoptive cell therapy or antibody-based immunomodulation in human disease.
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Project description:Naïve vs. 24 hr plate-bound anti-CD3 and soluble anti-CD28 activated CD8+ T cells were pulsed with [U-13C]glucose. Intracellular glucose-derived glutamate levels were quantified using MS.
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Project description:The aim of the study was to compare the two different costimuli anti-CD28 (costimulus 2a) and IL-2 (costimulus 2b) – in the presence of a suboptimal anti-CD3 signal (signal 1) – on the de novo activation of freshly purified human naive T cells. To this end, purified human naive T cells were co-incubated for seven days with a tumor vaccine which consisted of gamma-irradiated and Newcastle Disease Virus (NDV)-infected MCF-7 cells (a well-defined mammacarcinoma cell line). The gamma-irradiation dose was 200 Gray (Gy) to suppress the proliferation capacity of the vaccine cells (although the vaccine cells are not killed by such a procedure but still survive for several days); NDV-infection was performed at a dose of 100 hemagglutination units (HU) per 10^7 vaccine cells. The latter led – among others – to the upregulation of the viral surface molecules hemagglutinin neuraminidase (HN) and the fusion protein (F), both of which can serve for the attachment of fusion proteins delivering the activation signals to the naive T cells. The bispecific (bs) fusion proteins used in this study were of the single chain (scFv) format, binding with one arm to the viral HN molecule (for the attachment to the vaccine cells), and with the other arm either to the T cell receptor (TCR)-associated CD3 complex [as a surrogate of a major histocompatibility complex (MHC)-presented peptide recognized by the TCR] (bsHN-CD3), or to the costimulatory molecule CD28 (bsHN-CD28). Furthermore, a bispecific fusion protein containing the human interleukin (IL)-2 (bsHN-IL-2, a so-called immunocytokine) was used. The gene expression analysis of the differentially activated naive T cells revealed that in the presence of a suboptimal dose of anti-CD3 the two costimuli anti-CD28 (sample d7-S2_280705) and IL-2 (sample d7-S3_280705) led to a highly redundant pattern of gene upregulation in comparison to control samples in which naive T cells received only anti-CD3 (sample d7-S4_280705), anti-CD28 (sample d7-S5_280705) or IL-2 (sample d7-S6_280705) signals alone, or no signal at all (i.e. only vaccine cells; sample d7-S7_280705). All signals were compared to the reference sample which consisited of freshly isolated, non-activated naive T cells (sample d0-S1_280705). Global analysis of the gene expression showed that full naive T cell activation by anti-CD3/anti-CD28 and anti-CD3/IL-2 led to a significant upregulation of 76 and 71 genes, respectively (upregulation was considered to be significant if the relative gene expression was more than 5-fold than in the reference sample). However, the suboptimal anti-CD3 stimulus alone upregulated only 31 genes, the anti-CD28 stimulus alone only 6 genes, and the IL-2 stimulus alone only 22 genes. Naive T cells that reveived virus-modified vaccine cells alone upregulated 18 genes. Equally upregulated genes in anti-CD3/anti-CD28 and anti-CD3/IL-2 activated naive T cells comprised genes coding for both (i) signalling and (ii) effector molecules. Concerning signalling molecules, both costimuli induced the nuclear factor (NF)-kappa B and nuclear factor of activated T cells (NF-AT) pathway via the key enzymes protein kinase C (PKC)-theta and phospholipase C (PLC)-gamma 1, respectively. Of special note was that signalling molecules of the CD28-mediated stress-activated protein kinase (Sapk) pathway, namely Vav-1, Rac-1 and Jnk-2, were also upregulated by IL-2 costimulation. Upregulated genes coding for effector molecules could be classified into different functional groups: namely regulators of apoptosis, cell adhesion, receptors/ligands and cytokines/chemokines. Some examples of effector molecule-coding genes similarly upregulated in anti-CD3/anti-CD28 and anti-CD3/IL-2 stimulated naive T cells, respectively, were for instance the cell adhesion molecules LFA-1 and CD2, or members of the TNF and TNF receptor superfamilies such as CD27, CD70, CD40 ligand, Fas ligand, as well as TNF-alpha and TNF-beta (and their corresponding receptors). Among apoptosis-related genes, the anti-apoptotic gene bcl-XL as well as the pro-apoptotic gene caspase 9 were upregulated. The latter – together with the observed upregulation of cytotoxic T lymphocytes-associated protein (CTLA)-4 – might be interpreted as an indication of cellular events occurring seven days after stimulation which are aiming at termination of the response. Furthermore, the microarray analysis also revealed and upregulation of the receptor for interferon (IFN)-gamma inducible protein of 10 kDa (IP-10), namely CXCR3, of the IL-12 receptor beta-chain and of the IL-15 receptor alpha-chain; these are often seen in close association with T cell activation in general, with T cell proliferation and with generation of memory T cells. It is also of interest to mention the upregulation of beta-actin which is required for a re-organization of the cytoskeleton and the 40-fold upregulation of the metabolic enzyme glyceraldehye-3-phosphate dehydrogenase (GAPDH) which provides ATP necessary for the increased metabolism of the activated cells. A summary of the interesting gene subset is attached as a supplementary table (including the pairwise compared normalized data). In summary, these data suggest a synergism and cross-talk between the two costimulatory pathways mediated by anti-CD28/CD28 and IL-2/IL-2 receptor, respectively. Keywords: Human naive T cells, activation, costimulation, anti-CD28, IL-2, signal transduction, tumor vaccine, immunocytokine
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Project description:The local mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TILs) and responsiveness to PD-1 blockade remain partly elucidated. In human ovarian cancer we show that tumor-reactive intraepithelial (ie)CD8+ TILs engaged by antigen are polyfunctional and upregulate PD-1, which restrains their effectiveness. PD-1+ TILs exhibit a continuum of TCR-engaged/exhausted states with variable effector fitness related to CD28 costimulation, which they receive in intraepithelial niches involving myeloid antigen-presenting cells (mAPC). Following PD-1 blockade, activation of TILs requires CD28 costimulation mediated in situ by tumor mAPCs, which is locally enhanced by CTLA-4 blockade. CD40 ligand also amplifies TIL responses in situ, especially in tumors in which mAPCs are not activated. Thus, dysfunctional and exhausted TILs, in a state of TCR engagement but without proper CD28 costimulation by mAPCs in situ, are unlikely to fully benefit from PD-1 blockade.
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