CXCR6 Positions Cytotoxic T Cells to Receive Critical Survival Signals in the Tumor Microenvironment
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE179111 | GEO | 2021/06/30
REPOSITORIES: GEO
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Project description:T cell antigen-receptor (TCR) and cytokine receptor engagement trigger large changes in Serine/Threonine kinase signalling networks to drive T cell activation and differentiation. The role of only few kinase signalling pathways have been studied in detail, and in this context, Pim kinases are an interesting, yet understudied, family of Serine/Threonine kinases, with reported roles in key processes including survival, proliferation, metabolism across a range of cell types. T lymphocytes predominantly express PIM1 and PIM2, which are rapidly induced by TCR, costimulation and cytokine signalling. Using high-resolution mass spectrometry and RNAseq we systematically examine the impact of Pim1/Pim2 double deficiency on in vitro differentiated cytotoxic T lymphocytes (CTL) expanded in the cytokines IL-2 and IL-15 to generate effector or memory T cells respectively. We find that Pim kinases are dispensable for IL-15-driven memory cell differentiation, but that Pim1/2-deficiency has a selective impact on the transcriptome and proteome of IL-2 driven effector CD8 T cells. ~75% of Pim kinase-regulated proteins were not predicted by differences in mRNA in IL-2 expanded CTL. These included proteins that are key for effector cell function: glucose transporters SLC2A1 and SLC2A3 and key effector molecules Granzyme A and B. We find that Pim kinases have this effect via control of protein translation. Another key finding was that the mRNA for key T cell homing receptors Ccr7, S1pr1 and CD62L was increased in Pim1/2-deficienct T cells and that this functionally enhancing homing to secondary lymphoid organs.
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Project description:The strength of T cell stimulation determines IL-7 responsiveness, recall potential and lineage commitment of primed human CD4+IL-7Rhi T cells; We analyzed how the strength of antigenic stimulation - as determined by dendritic cell (DC) number, DC maturation state and antigen concentration - controls in human CD4+ T cells IL-7R? expression and responsiveness to IL-7, IL-15 and antigen. We found that T cells primed by different strengths of stimulation expressed IL-7R? in different proportions and preferentially on cells that maintained expression of the central memory marker CCR7. However, while CCR7+IL-7Rhi cells generated at high strength of stimulation proliferated vigorously in response to IL-7 or IL-15, CCR7+IL-7Rhi cells generated at low strength of stimulation responded poorly. High cytokine responsiveness was associated with reduced PTEN expression and enhanced s6-kinase activation, consistent with efficient receptor coupling to downstream signalling pathways. Interestingly, while intermediate-stimulated CCR7+IL-7Rhi cells were non-polarized, self-renewed with IL-7 and expanded with antigen, high-stimulated cells generated Th1 effector cells with cytokines but showed impaired IL-2 production and survival with antigen. Gene expression analysis suggested that high-stimulated cells represented pre-Th1 cells with low recall potential and high metabolic state. Taken together these results demonstrate that IL-7 receptor expression and coupling are instructed in T cells by the strength of stimulation and suggest that memory subsets may derive from CCR7+IL-7Rhi precursors that received different strengths of stimulation. Experiment Overall Design: two samples treated with weaker dendritic stimulus, two samples treated with stonger dendritic stimulus.
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Project description:Mathematical modeling of immune modulation by glucocorticoids
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Abstract
The cellular and molecular mechanisms of immunomodulatory actions of glucocorticoids (GC) remain to be identified. Using our experimental findings, a mathematical model based on a system of ordinary differential equations for characterization of the regulation of anti-tumor immune activity by the both direct and indirect GC effects was generated to study the effects of GC treatment on effector CD8+ T cells, GC-generated tolerogenic dendritic cells (DC), regulatory T cells and the growth of lymphoma cells. In addition, we compared the data from in vivo and in silico experiments. The mathematical simulations indicated that treatment with GCs may suppress anti-tumor immune response in a dose-dependent manner. The model simulations were in line with earlier experimental observations of inhibitory effects of GCs on T and NK cells and DCs. The results of this study might be useful for predicting clinical outcomes in patients receiving GC therapy.
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Project description:The strength of T cell stimulation determines IL-7 responsiveness, recall potential and lineage commitment of primed human CD4+IL-7Rhi T cells We analyzed how the strength of antigenic stimulation - as determined by dendritic cell (DC) number, DC maturation state and antigen concentration - controls in human CD4+ T cells IL-7R? expression and responsiveness to IL-7, IL-15 and antigen. We found that T cells primed by different strengths of stimulation expressed IL-7R? in different proportions and preferentially on cells that maintained expression of the central memory marker CCR7. However, while CCR7+IL-7Rhi cells generated at high strength of stimulation proliferated vigorously in response to IL-7 or IL-15, CCR7+IL-7Rhi cells generated at low strength of stimulation responded poorly. High cytokine responsiveness was associated with reduced PTEN expression and enhanced s6-kinase activation, consistent with efficient receptor coupling to downstream signalling pathways. Interestingly, while intermediate-stimulated CCR7+IL-7Rhi cells were non-polarized, self-renewed with IL-7 and expanded with antigen, high-stimulated cells generated Th1 effector cells with cytokines but showed impaired IL-2 production and survival with antigen. Gene expression analysis suggested that high-stimulated cells represented pre-Th1 cells with low recall potential and high metabolic state. Taken together these results demonstrate that IL-7 receptor expression and coupling are instructed in T cells by the strength of stimulation and suggest that memory subsets may derive from CCR7+IL-7Rhi precursors that received different strengths of stimulation. Keywords: comparison
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Project description:Comparison of genome-wide mRNA expresson between tumor-infiltrating CD8+ T cells from the tumor (hypofunctional T cells) and periphery (functional T cells) Mechanisms of self-tolerance often result in CD8+ tumor-infiltrating lymphocytes (TIL) with a hypofunctional phenotype incapable of tumor clearance. Using a solid tumor model in mice, we found that CD8+ T cells became tolerized in less than 24 hours in an established tumor environment. To define the collective impact of pathways suppressing TIL function, we compared genome-wide mRNA expression of tumor-specific CD8+ T cells from the tumor and periphery. Notably, gene expression induced during TIL hypofunction more closely resembled self-tolerance than viral-exhaustion. Differential gene expression was refined to identify a core set of genes that defined hypofunctional TIL; these data comprise the first âmolecular profileâ of tumor-specific TIL that are naturally responding and represent a polyclonal repertoire. The molecular profile of TIL was further dissected to determine the extent of overlap and distinction between pathways that collectively restrict T cell functions. As suggested by the molecular profile of TIL, protein expression of inhibitory receptor LAG-3 was differentially regulated throughout prolonged late-G1/early-S phase of the cell cycle. Our data may accelerate efficient identification of combination therapies to boost anti-tumor function of TIL specifically against tumor cells. 4 samples, 3 biological replicates per group.
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