Unknown,Transcriptomics,Genomics,Proteomics

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TLR4 ligands LPS and MPLA differentially regualte effector and memory CD8 T cell differentiation

ABSTRACT: Here we implemented a simple dendritic cell (DC)-mediated immunization approach to study the effects of commonly used adjuvants, Toll like receptor (TLR) ligands, on effector CD8 T cell differentiation and memory T cell development. To our surprise, we found that the TLR4 ligand LPS was far more superior to other TLR ligands in generating memory CD8 T cells upon immunization. LPS boosted clonal expansion similar to the other adjuvants, but fewer of the activated CD8 T cells died during contraction, generating a larger pool of memory cells. Intriguingly, monophosphoryl lipid A (MPLA), another TLR4 ligand, enhanced clonal expansion of effector CD8 T cells, but also promoted their terminal differentiation and contraction; thus, fewer memory CD8 T cells formed and MPLA-primed animals were less protected against secondary infection compared to those primed with LPS. Furthermore, gene expression profiling revealed that LPS-primed effector cells displayed a stronger pro-memory gene expression signature, whereas the gene expression profile of MPLA-primed effector cells had aligned closer with terminal effector CD8 T cells. Mice that contain small number of P14 CD8 T cells were immunized with DC-33 either alone or in combination with LPS or MPLA. KLRG1loIL-7Rhi MPECs were purified by FACS sort, and mRNA isolated from MPECs was subjected to whole-genome expression profiling using Illumina MouseWG-6 v2.0 Expression BeadChip.

ORGANISM(S): Mus musculus

SUBMITTER: Hailong Meng

PROVIDER: E-GEOD-50764 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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TLR4 ligands lipopolysaccharide and monophosphoryl lipid a differentially regulate effector and memory CD8+ T Cell differentiation.

Cui Weiguo W Joshi Nikhil S NS Liu Ying Y Meng Hailong H Kleinstein Steven H SH Kaech Susan M SM

Journal of immunology (Baltimore, Md. : 1950) 20140321 9

Vaccines formulated with nonreplicating pathogens require adjuvants to help bolster immunogenicity. The role of adjuvants in Ab production has been well studied, but how they influence memory CD8(+) T cell differentiation remains poorly defined. In this study we implemented dendritic cell-mediated immunization to study the effects of commonly used adjuvants, TLR ligands, on effector and memory CD8(+) T cell differentiation in mice. Intriguingly, we found that the TLR4 ligand LPS was far more sup ...[more]

PMID: 24659688

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Project description:During a T cell response, naÃ¯ve CD8 T cells differentiate into effector cells. Subsequently, a subset of effector cells termed memory precursor effector cells (MPECs) further differentiates into functionally mature memory CD8 T cells. The transcriptional network underlying this carefully scripted process is not well understood. Here, we report that the transcription factor FoxO1 plays an integral role in facilitating effector to memory transition and functional maturation of memory CD4 and CD8 T cells. We find that FoxO1 is not required for differentiation of effector cells, but in the absence of FoxO1, memory CD8 T cells displayed features of scenescence and progressive attrition in polyfunctionality, which in turn led to impared recall responses and poor protective immunity. These data suggest that FoxO1 is essential for active maintenance of functional CD8 T cell memory and protective immunity. Under competing conditions in bone marrow Single-cell suspensions from splenocytes of eight samples WT (control) and FoxO1-/- (experimental) LCMV-immune mice were prepared using standard procedures. CD8 T cells were then isoloated using Thy1.2 (CD90.2) (30-H12) microbeads (Miltenyi Biotec). Cells were then stained with anti-CD8, anti-CD44 and Db/NP396 MHC class I tetramer. Activated (CD8+CD44hi), naive (CD8+CD44lo), and virus-specific CD8 T cells were sorted using FACSAria II instrument (BD Biosciences). The purity of the cells was >95%. Total RNA was extracted from the sorted cells by Trizol Reagent. RNA samples were reverse transcribed and Cy3-labeled cDNAs were hyrbidized to Agilent whole Mouse Genome Oligo Microarrays. Fluorscence signals were detected using Agilent's Microarray Scanner system, data was analyzed using the Rosetta Resolver gene expression data analysis system and genes with a fold change < and p-values <0.01 were identified. Microarray data discussed in the paper is focused on virus-specific memory CD8 T cells from samples WT_Tet_2 vs KO_Tet_2.

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TLR4 ligands LPS and MPLA differentially regualte effector and memory CD8 T cell differentiation

Publications

TLR4 ligands lipopolysaccharide and monophosphoryl lipid a differentially regulate effector and memory CD8+ T Cell differentiation.

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