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Memory T cell RNA rearrangement by hn RNP LL

ABSTRACT: Immunological Memory is characterized by a heightened recall response to a previously encountered antigen, resulting from clonal expansion of antigen-specific lymphocytes and differentiation into specialized memory cells. Differentiation of memory B cells involves irreversible encountered antigen, resulting from clonal expansion of antigen-specific lymphocytes and differentiation into specialised memory cells. Differentiation of memory B cells involves irrversible DNA rearrangements and mutations, but differentiation of memory T cells is less understood. In an ENU screen for mouse mutations affecting the proportion of T cells with known memory cell markers, such as the alternative spliced Ptprc isoform CD45RO, we identified an inducible RNA-binding protein of previously unknown function, hnRNPLL (gene symbol Hnrpll), whose mutation abolishes the regulated silencing of CD45RABC exons in T cells and other leukocytes. In the mutant, a single amino acid substitution destabilizes an RNA-recognition domain that binds with micromolar affinity to RNA containing the Ptprc ARS exon silencing sequence. Hnrpll mutations selectively diminishes T cell accumulation in peripheral lymphoid tissues but not proliferation. Exon array analysis of Hnrpll mutant naive and memory T cells reveals an extensive program of alternative mRNA splicing in memory T cells coordinated by hnRNPLL. A remarkable overlap with alternative splicing in neural tissues may reflect a co-opted strategy of RNA rearrangement for achieving immunological memory in T cells. Keywords: Memory; T cell; Immunological memory; Cell differentiation; Alternative splicing; T cell survival; Neuron; Brain; RNA-binding; Exon silencing sequence; Mouse mutation; Exon Microarray

ORGANISM(S): Mus musculus

PROVIDER: GSE13416 | GEO | 2008/12/31

SECONDARY ACCESSION(S): PRJNA110063

REPOSITORIES: GEO

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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.

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Memory T cell RNA rearrangement by hn RNP LL

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