Cell-intrinsic Tim-3 is Required for Optimal CD8 Response to Acute LCMV Infection
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PROVIDER: PRJNA1283055 | ENA |
REPOSITORIES: ENA
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Project description:Cell-intrinsic Tim-3 is Required for Optimal CD8 Response to Acute LCMV Infection [TCRseq]
| PRJNA1282607 | ENA
Project description:Cell-intrinsic Tim-3 is Required for Optimal CD8 Response to Acute LCMV Infection [RNAseq]
| PRJNA1282608 | ENA
Project description:Tim-3, or transmembrane immunoglobulin and mucin domain-3, is a type I membrane protein expressed by various immune cell types and which is best known as a negative regulator of anti-tumor immunity. However, Tim-3 also has a co-stimulatory role in T cells under some conditions, via enhancement of PI3K signaling. We hypothesize that Tim-3 signaling enhances CD8+ T cell activation during acute infection and contributes to enhanced CD8+ effector function. To test this hypothesis, we used LCMV-specific TCR transgenic (P14) mice expressing a truncated, non-signaling, allele of Tim-3 or CD8-specific deletion of Tim-3. CD8+ T cell effectors were analyzed by flow cytometry after acute infection with LCMV Armstrong. At the effector stage, endogenous Tim-3+ T cells had increased expression of effector CD8 markers, compared with Tim-3 negative cells. Tim-3 knockout mice also showed a significantly lower number of LCMV-specific T cells. Additionally, endogenous Tim-3+ T cells were also significantly better at cytokine production and had increased cytotoxicity. Tim-3 expression correlated with better cell survival in homeostatic conditions after the virus had been cleared. Bulk RNA sequencing and TCR sequencing revealed that Tim-3-expressing effector CD8+ T cells had a distinct pattern of effector gene upregulation, with increased expansion of a subset of TCR clones. Mechanistically, Tim-3 signals enhances phosphorylation of Foxo1, inhibiting its entry into the nucleus, conferring enhanced effector function. Thus, Tim-3 signaling contributes positively to an effective CD8+ T cell response during acute infection. These findings may lead to a better understanding of CD8+ T cell function in different settings, including in tumors.
2025-07-01 | GSE301002 | GEO
Project description:Tim-3, or transmembrane immunoglobulin and mucin domain-3, is a type I membrane protein expressed by various immune cell types and which is best known as a negative regulator of anti-tumor immunity. However, Tim-3 also has a co-stimulatory role in T cells under some conditions, via enhancement of PI3K signaling. We hypothesize that Tim-3 signaling enhances CD8+ T cell activation during acute infection and contributes to enhanced CD8+ effector function. To test this hypothesis, we used LCMV-specific TCR transgenic (P14) mice expressing a truncated, non-signaling, allele of Tim-3 or CD8-specific deletion of Tim-3. CD8+ T cell effectors were analyzed by flow cytometry after acute infection with LCMV Armstrong. At the effector stage, endogenous Tim-3+ T cells had increased expression of effector CD8 markers, compared with Tim-3 negative cells. Tim-3 knockout mice also showed a significantly lower number of LCMV-specific T cells. Additionally, endogenous Tim-3+ T cells were also significantly better at cytokine production and had increased cytotoxicity. Tim-3 expression correlated with better cell survival in homeostatic conditions after the virus had been cleared. Bulk RNA sequencing and TCR sequencing revealed that Tim-3-expressing effector CD8+ T cells had a distinct pattern of effector gene upregulation, with increased expansion of a subset of TCR clones. Mechanistically, Tim-3 signals enhances phosphorylation of Foxo1, inhibiting its entry into the nucleus, conferring enhanced effector function. Thus, Tim-3 signaling contributes positively to an effective CD8+ T cell response during acute infection. These findings may lead to a better understanding of CD8+ T cell function in different settings, including in tumors.
2025-07-01 | GSE300893 | GEO
Project description:Tim-3, or transmembrane immunoglobulin and mucin domain-3, is a type I membrane protein expressed by various immune cell types and which is best known as a negative regulator of anti-tumor immunity. However, Tim-3 also has a co-stimulatory role in T cells under some conditions, via enhancement of PI3K signaling. We hypothesize that Tim-3 signaling enhances CD8+ T cell activation during acute infection and contributes to enhanced CD8+ effector function. To test this hypothesis, we used LCMV-specific TCR transgenic (P14) mice expressing a truncated, non-signaling, allele of Tim-3 or CD8-specific deletion of Tim-3. CD8+ T cell effectors were analyzed by flow cytometry after acute infection with LCMV Armstrong. At the effector stage, endogenous Tim-3+ T cells had increased expression of effector CD8 markers, compared with Tim-3 negative cells. Tim-3 knockout mice also showed a significantly lower number of LCMV-specific T cells. Additionally, endogenous Tim-3+ T cells were also significantly better at cytokine production and had increased cytotoxicity. Tim-3 expression correlated with better cell survival in homeostatic conditions after the virus had been cleared. Bulk RNA sequencing and TCR sequencing revealed that Tim-3-expressing effector CD8+ T cells had a distinct pattern of effector gene upregulation, with increased expansion of a subset of TCR clones. Mechanistically, Tim-3 signals enhances phosphorylation of Foxo1, inhibiting its entry into the nucleus, conferring enhanced effector function. Thus, Tim-3 signaling contributes positively to an effective CD8+ T cell response during acute infection. These findings may lead to a better understanding of CD8+ T cell function in different settings, including in tumors.
2025-07-01 | GSE300892 | GEO
Project description:RAW264.7 cell was stably transfected with Tim-3 siRNA(SI) or negative control(NC) and were analyzed for microRNA expression Differerently expressed microRNA in Tim-3 knockdown RAW264.7 cells were summarized and were used for further analysis RAW264.7 cells stably transfected with Tim-3 siRNA(SI) or negative control(NC) and were used to collect microRNA without any other treatment
2016-01-14 | E-GEOD-76839 | biostudies-arrayexpress
Project description:Investigation of whole genome gene expression level changes in a Tim-3 knockdown RAW264.7 cell, compared to control siRNA transfected RAW264.7 cell. The Tim-3 knockdown of this cell render it hyper-reactive to TLR stimulation. Tim-3 knockdown analyzed in this study are further described in Li Y, Feng J, Geng S, Geng S, Wei H, Chen G, Li X, Wang L, Wang R, Peng H, Han G, Shen B, Li Y. 2011. The N- and C-terminal carbohydrate recognition domains of galectin-9 contribute differently to its multiple functions in innate immunity and adaptive immunity. Mol Immunol. 48(4):670-7. (PID 21146220) A six chip study using total RNA recovered from Tim-3 knockdown and control RAW264.7 cells. There are 135,000 probes in a chip,each chip measures the expression level of 27526 genes of mouse from Nimblegen. Fold-change screening between the two groups obtained from the experiment. The threshold used to screen up or down regulated genes is Fold changeM-oM-<M-^-oM-<M-^]2.0
2012-12-05 | E-GEOD-42729 | biostudies-arrayexpress
Project description:TIM-3 is known to be expressed on dendritic cells, monocytes, melanoma cells, mast cells and on activated Th1 cells. In activated Th1 cells, stimulating TIM-3 by one of its ligands, galectin-9, leads to apoptosis and thus it plays a central role in terminating Th1-type immune responses. Interestingly, in IgE/antigen-activated mast cells TIM-3 enhances the production of IL-13 and IL-4. To get a more complete picture about the gene expression changes induced by TIM-3 in mast cells, in vitro differentiated mouse immature mast cells were stimulated by an agonist anti-TIM-3 antibody and IgE-sensitized mouse immature mast cells were activated by antigen and an agonist anti-TIM-3 antibody for 2 or 16 hours (overnight). Experiment Overall Design: Bone marrow cells were differentiated in RPMI + 10% FCS + 5 ng/ml mouse IL-3 + 40 ng/ml mouse SCF for >4 weeks. The purity of the cell cultures was >90% at this time point (FcERIa+/c-kit+ cells). These in vitro-differentiated immature mast cells were then treated by either control goat IgG or an agonist anti-mouse TIM-3 antibody (RnD Systems, 15 ug/ml for 2 or 16 hours). For the IgE/antigen-activated mouse mast cells, these in vitro-differentiated immature mast cells were sensitized by 5 ug/ml anti-DNP IgE (Sigma) for 1 hour and then treated with 100 ng/ml DNP-HSA (antigen, Sigma) and either control goat IgG or an agonist anti-mouse TIM-3 antibody (RnD Systems, 15 ug/ml) for 2 or 16 hours. The anti-TIM-3 samples were labeled by Cy5 and they were compared to the Cy3-labeled, goat IgG controls in a dual-color, paired experimental setup. The Agilent Whole Mouse Genome 4x44K expression microarray kit and Dual-Color Protocol version 5.5 were used in the experiments.
2009-10-15 | E-GEOD-14438 | biostudies-arrayexpress
Project description:Exhaustion markers are expressed by T lymphocytes in Follicular Lymphoma (FL). Through these, TIM-3 has been recently identified as a poor pronostic factor when expressed by FL CD4+ T cells. Before this study, there was no molecular characterization of unstimulated CD8+ T cells, expressing - or not - TIM-3. We used microarrays to compare the global gene expression profile between CD8+TIM-3+ T cells and CD8+TIM-3- T cells freshly sorted from follicular lymphoma biopsies. Abstract from the associated publication: Up-regulation of T-cell immunoglobulin-3 (TIM-3) has been associated with negative regulation of the immune response in chronic infection and cancer, including lymphoma. Here, we investigated the possible correlation between TIM-3 expression by ex vivo cytotoxic T cells (CTL) from follicular lymphoma (FL) biopsies and their functional unresponsiveness that could limit the favorable impact of CTL on disease progression. We report a high percentage of CD8+TIM-3+ T cells in lymph nodes of FL patients. When compared to their CD8+TIM-3- counterparts, CD8+TIM-3+ T cells exhibited defective cytokine production following TCR engagement. Furthermore CD8+TIM-3+ T cells display ex vivo markers of lytic granule release and remain unresponsive to further TCR-induced activation of the lytic machinery. Although confocal microscopy showed that TIM-3 expression on CD8+ T cells correlated with minor alterations of immunological synapse, a selective reduction of ERK signaling in CD8+TIM-3+ T cells was observed by phospho-flow analysis. Finally, short relapse free survival despite rituximab(R)-chemotherapy was observed in patients with high content of TIM-3+ cells and a poor infiltrate of granzyme B+ T cells in FL lymph nodes. Together, our data indicate that, besides selective TCR early signaling defects, TIM-3 expression correlates with unresponsiveness of ex vivo CD8+ T cells in FL. They show that scores based on the combination of exhaustion and cytolytic markers in FL microenvironment might be instrumental to identify patients at early risk of relapses following R-chemotherapy.
2016-12-15 | GSE84072 | GEO
Project description:To identify mechanisms behind immunosuppression during virus infections, we infected mice with LCMV-Armstrong and LCMV-Clone 13 expression patterns. LCMV-Armstrong induces a T-cell reaction that resolves infection within 8-10 days, while LCMV-Clone13 generates a persisten infection through immunosuppression. We used microarray to uncover splenic gene expression patterns specific to each LCMV infection at 5, 9, and 30 days C57BL6 mice, 6-10 weeks old, were infected with LCMV-Armstrong and LCMV-Clone 13 or left uninfected (naïve). At days 5, 9, and 30 whole spleens were harvested for RNA extraction and hybridization on Affymetric microarray.
2013-02-15 | E-GEOD-44322 | biostudies-arrayexpress