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The Transcription Factor ZFfx Regulates Peripheral T Cell Self-renewal and Proliferation

ABSTRACT: Peripheral T lymphocytes share many functional properties with hematopoietic stem cells (HSCs), including long-term maintenance, quiescence, and latent proliferative potential. In addition, peripheral T cells retain the capacity for further differentiation into a variety of subsets, much like HSCs. While the similarities between T cells and HSC has long been hypothesized, the potential common genetic regulation of HSCs and T cells has not been widely explored. We have studied the T cell-intrinsic role of Zfx, a transcription factor specifically required for HSC maintenance. We report that T cell-specific deletion of Zfx caused age-dependent depletion of naÃ¯ve peripheral T cells. Zfx-deficient T cells failed to undergo homeostatic proliferation in a lymphopenic environment, and showed impaired antigen-specific expansion and memory response. In addition, the invariant natural killer T cell (iNKT) cell compartment was severely reduced. Transcriptome analysis identified target genes of Zfx in T cells which are shared with HSCs. Zfx-deficient T cells also revealed activation of the stress response, elevated expression of cell cycle inhibitor Cdkn1a/p21 and reduced telomerase activity. These studies identify Zfx as an important regulator of peripheral T cell maintenance and expansion, and highlight the common molecular basis of HSC and T cell homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE114785 | GEO | 2018/07/05

REPOSITORIES: GEO

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Project description:The development, homeostasis and function of B lymphocytes involve multiple rounds of B cell receptor (BCR)-controlled proliferation and prolonged maintenance. We analyzed the role of transcription factor Zfx, a recently identified regulator of stem cell maintenance, in B cell development and homeostasis. Conditional Zfx deletion in the bone marrow blocked B cell development at the pre-BCR selection checkpoint. Zfx deficiency in peripheral B cells caused impaired generation of the B-1 cell lineage, accelerated B cell turnover, depletion of mature recirculating cells, and delayed T-dependent antibody responses. Zfx-deficient B cells showed normal proximal BCR signaling, but impaired BCR-induced proliferation and survival. This was accompanied by aberrantly enhanced and prolonged integrated stress response, and delayed induction of Cyclin D2 and Bcl-xL proteins. Thus, Zfx restrains the stress response and couples antigen receptor signaling to B cell expansion and maintenance during development and peripheral homeostasis. Keywords: Expression profiling by array For global gene expression analysis, 2.5 x 105 flow-sorted follicular B cells (B220+ AA4.1- CD23hi CD21int) were cultured in 200 μL B cell media containing 10 μg/mL α-IgM for 0, 2, and 12 hrs. Cells were harvested in Trizol (Invitrogen). Total RNA was isolated using Trizol (Invitrogen), and 100 ng of each RNA sample were used for reverse transcription and two rounds of linear antisense RNA amplification/labeling (Ambion). The aRNA was amplified without labeling in the first round, and then labeled with Biotin-16-UTP(Roche Applied Sciences) and Biotin-11-CTP (PerkinElmer Life Sciences) in the second round. Labeled aRNA was fragmented in RNA Fragmentation Buffer (QIAGEN) prior to hybridization. Labeled RNA samples (10 ug/array) were hybridized in duplicate to Mouse Genome 430 2.0 arrays (Affymetrix) at the Columbia University Microarray Project core facility according to the manufacturer's instructions. Quality control and normalization were performed using positive and negative hybridization controls (Affymetrix) spiked into the RNA prior to labeling. Linear amplification of RNA was confirmed for every sample. Array scanning and raw data processing were done using GCOS 1.4 software (Affymetrix).

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The Transcription Factor ZFfx Regulates Peripheral T Cell Self-renewal and Proliferation

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