Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcriptional profiling of p56lck-deficient regulatory and memory T cells

ABSTRACT: Signaling through the T cell antigen receptor is essential for the formation of regulatory T (Treg) cells in the thymus and for their involvement in antigen-directed suppression of immune responses. Using a conditional null allele of the gene encoding p56Lck we show here that T cell antigen receptor (TCR) signaling is also essential for sustaining the phenotype and homeostasis of Treg cells. Inactivation of p56Lck in Treg cells resulted in large-scale changes in their gene expression profile, blocked their capacity to suppress responses, inhibited their proliferation, and caused them to redistribute in the body. The results make clear multiple aspects of the Treg cell phenotype that are dependent on a sustained capacity to respond through their TCRs. Keywords: Genetic deficiency of p56lck Two-condition experiment: wild-type memory or regulatory T cells versus lck-deficient memory or regulatory T cells.

ORGANISM(S): Mus musculus

SUBMITTER: Mark Klinger

PROVIDER: E-GEOD-13645 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Impact of the TCR signal on regulatory T cell homeostasis, function, and trafficking.

Kim Joong Kyu JK Klinger Mark M Benjamin Jonathan J Xiao Yuanyuan Y Erle David J DJ Littman Dan R DR Killeen Nigel N

PloS one 20090811 8

Signaling through the T cell antigen receptor (TCR) is important for the homeostasis of naïve and memory CD4(+) T cells. The significance of TCR signaling in regulatory T (Treg) cells has not been systematically addressed. Using an Ox40-cre allele that is prominently expressed in Treg cells, and a conditional null allele of the gene encoding p56(Lck), we have examined the importance of TCR signaling in Treg cells. Inactivation of p56(Lck) resulted in abnormal Treg homeostasis characterized by im ...[more]

PMID: 19668367

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Project description:Immune memory cells are poised to rapidly expand and elaborate effector functions upon reinfection. However, despite heightened readiness to respond, memory cells exist in a functionally quiescent state. The paradigm is that memory cells remain inactive due to lack of TCR stimuli. Here we report a unique role of Tregs in orchestrating memory quiescence by inhibiting effector and proliferation programs through CTLA-4. Loss of Tregs resulted in activation of genome-wide transcriptional programs characteristic of potent effectors, and both developing and established memory quickly reverted to a terminally differentiated (KLRG-1hi/IL-7R±lo/GzmBhi) phenotype, with compromised metabolic fitness, longevity, polyfunctionality and protective efficacy. CTLA-4, an inhibitory receptor overexpressed on Tregs, functionally replaced Tregs in trans to rescue Treg-less memory defects and restore homeostasis of secondary mediators as well. These studies present CD28-CTLA-4-CD80/CD86 axis as a novel target to potentially accelerate vaccine-induced immunity and improve T-cell memory quality in current cancer immunotherapies proposing transient Treg-depletion. We used microarray analysis to detail the global programming of gene expression in LCMV GP33-specific CD8 T cells differentiated in the presence or absence of regulatory T cells Differentiation of memory CD8 T cells entails a progressive transition of highly activated effector program to a quiescent memory program. A key question in the field is to understand the factors that aid in the differentiation of memory cells from effector cells. It is a generally accepted paradigm that effector cells transition to a memory state by default after antigen clearance, since TCR stimuli is the key driver of effector programs in CD8 T cells. We hypothesized that the effector to memory transition of CD8 T cells involves active immunological brakes through regulatory T cells (Tregs) that allow the highly activated effector cells to convert into quiescent memory cells. To address this hypothesis, we used FoxP3-DTR mice to deplete Tregs during the window following antigen clearance, during which the effector CD8 T cells convert to long-lived memory cells. To get a deeper understanding of the global transcriptome of CD8 T cells as they transition from an effector to a memory state, we isolated and arrayed the antigen-specific CD8 T cells at day 16 post-infection that have experienced the transitional environment with and without the presence of Tregs.

Dataset Information

Transcriptional profiling of p56lck-deficient regulatory and memory T cells

Publications

Impact of the TCR signal on regulatory T cell homeostasis, function, and trafficking.

Similar Datasets

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