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Transcription factor Zfx controls BCR-induced proliferation and survival of B lymphocytes.

ABSTRACT: 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 hematopoietic stem cell maintenance, in B-cell development and homeostasis. Panhematopoietic or B cell-specific deletion of Zfx in the bone marrow blocked B-cell development at the pre-BCR selection checkpoint. Zfx deficiency in peripheral B cells caused accelerated B-cell turnover, depletion of mature recirculating B cells, and delayed T-dependent antibody responses. In addition, the numbers and function of B-1 cell lineage were reduced. Zfx-deficient B cells showed normal proximal BCR signaling, but impaired BCR-induced proliferation and survival in vitro. This was accompanied by aberrantly enhanced and prolonged integrated stress response and by delayed induction of cyclin D2 and Bcl-xL proteins. Thus, Zfx restrains the stress response and couples antigen receptor signaling to cell expansion and maintenance during B-cell development and peripheral homeostasis. These results identify a novel transcriptional regulator of the B-cell lineage and highlight the common genetic control of stem cell maintenance and lymphocyte homeostasis.

SUBMITTER: Arenzana TL

PROVIDER: S-EPMC2700322 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Transcription factor Zfx controls BCR-induced proliferation and survival of B lymphocytes.

Arenzana Teresita L TL Smith-Raska Matthew R MR Reizis Boris B

Blood 20090327 23

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 hematopoietic stem cell maintenance, in B-cell development and homeostasis. Panhematopoietic or B cell-specific deletion of Zfx in the bone marrow blocked B-cell development at the pre-BCR selection checkpoint. Zfx deficiency in peripheral B cells caused ...[more]

PMID: 19329779

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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).

Project description:Recovery of the T lymphocyte compartment within a lymphopenic host by lymphopenia-induced proliferation (LIP) is regulated by inter- and intraclonal competition for limited resources, including homeostatic cytokines and peptide:MHC (pMHC) complexes with which the TCR can interact at least weakly to yield a tonic signal. Importantly, the process of LIP can synergize with other factors that promote T cell activation to drive inflammatory disease. While reconstitution of the lymphoid compartment of immune deficient Rag-/- mice by transfer of wild-type hematopoietic stem cells (HSC) does not generally result in an overt disease phenotype, transfer of HSC deficient in expression of the co-inhibitory molecule PD-1 results in severe systemic autoimmunity driven by newly generated T cells that emerge from the thymus into the periphery and undergo LIP. Importantly, autoimmunity does not appear to depend on a response to exogenous (i.e., gut flora-derived) antigens. PD-1 is well known to be upregulated during T cell activation in response to cognate antigens, but it is unclear whether PD-1 has a role in controlling LIP of T cells in the absence of cognate antigen, i.e., in response to tonic pMHC. We examined whether PD-1 controls LIP of newly generated T cells by controlling the response to tonic pMHC or the homeostatic cytokine IL-7. We found that PD-1-deficient T cells have a proliferative advantage over WT T cells during LIP and this effect is MHC-II dependent and independent of IL-7Rα signaling. Furthermore, our data suggest that signals through IL-7Rα can be dispensable for LIP and may instead be of increased importance for T cell survival in conditions of high competition for limited pMHC (e.g., post-LIP, in a lymphoreplete host). We hypothesize that autoimmunity post-PD-1-/- HSC transplant is the result of an overzealous T cell response to normally tonic self-pMHC precipitated by the synergy of LIP and PD-1 deficiency. Furthermore, potentiation of TCR signals in response to normally tonic self-pMHC may contribute to the success of PD-1 blockade in cancer immunotherapy.

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Transcription factor Zfx controls BCR-induced proliferation and survival of B lymphocytes.

Publications

Transcription factor Zfx controls BCR-induced proliferation and survival of B lymphocytes.

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