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Characterization of myeloid cells in acute and chronic LCMV infection by scRNA-seq

ABSTRACT: The immune response to a chronic viral infection is uniquely tailored to balance viral control and immunopathology. The role of myeloid cells in shaping the response to chronic viral infection, however, is poorly understood. Single-cell RNA sequencing of myeloid cells during acute and chronic LCMV infection was performed to address this question. We discovered a cluster of suppressive neutrophils that is enriched in chronic versus acute infection. Furthermore, suppressive neutrophils highly expressed the gene encoding PIM1, a kinase known to promote mitochondrial fitness and cell survival. Pharmacological inhibition of PIM1 selectively diminished suppressive neutrophil-mediated immunosuppression without affecting the function of monocytic myeloid derived suppressor cells (M-MDSCs). Decreased accumulation of suppressive neutrophils led to increased CD8 T cell function and viral control. Mechanistically, PIM kinase activity was required for maintaining fused mitochondrial networks in suppressive neutrophils, but not in M-MDSCs, and loss of PIM kinase function caused increased apoptosis of suppressive neutrophils.

ORGANISM(S): Mus musculus

PROVIDER: GSE167204 | GEO | 2021/05/05

REPOSITORIES: GEO

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Characterization of immune cells from an ICB responder and non-responder using scRNA-seq

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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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