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When T cells with CD4 markers are activated, they give rise to two types of effector cells: helper T cells and regulatory T cells. Meanwhile, T cells with CD8 markers differentiate into effector cytotoxic T cells. The differentiation of CD4 T cells into helper T cell subsets, such as Th1, Th2, and Th17 cells, is dependent on the antigen type, antigen-presenting cell, and regulatory cytokines.
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The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
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Related Experiment Video

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Cell geometry dictates TNFα-induced genome response.

Aninda Mitra1,2, Saradha Venkatachalapathy1, Prasuna Ratna1,2

  • 1Mechanobiology Institute, National University of Singapore, Singapore 117411.

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Cell shape influences how fibroblasts respond to tumor necrosis factor-alpha (TNFα) signaling. This geometry-dependent response affects key molecular pathways and cell proliferation, highlighting the interplay between physical and chemical cues.

Keywords:
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Area of Science:

  • Cellular and Molecular Physiology
  • Biophysics
  • Systems Biology

Background:

  • Cells integrate soluble and mechanical signals to control gene expression.
  • The combined effects of chemical and physical signals on cellular responses are not fully understood.
  • Tumor necrosis factor-alpha (TNFα) is a key cytokine involved in inflammation and immunity.

Purpose of the Study:

  • To investigate the cross-talk between cellular geometry and TNFα signaling pathways.
  • To determine how cell shape influences the nuclear translocation of transcription factors and gene expression.
  • To assess the functional impact of geometry on TNFα-induced fibroblast proliferation.

Main Methods:

  • NIH 3T3 fibroblasts were cultured in defined rectangular (anisotropic) and circular (isotropic) geometries.
  • Cells were stimulated with TNFα, and nuclear translocation of NFκB (p65) and MKL was analyzed.
  • Downstream gene expression patterns were profiled using transcriptomics; cell proliferation was measured.

Main Results:

  • TNFα induced geometry-dependent actin depolymerization, affecting IκB degradation and p65 nuclear translocation.
  • Cellular geometry modulated MKL nuclear exit and p65 sequestration at RNA-polymerase-II foci.
  • Global transcription profiles revealed geometry-dependent gene expression patterns in response to TNFα.

Conclusions:

  • Fibroblast cellular geometry significantly dictates cellular responses to TNFα signaling.
  • Distinct geometric constraints lead to differential regulation of molecular pathways and gene expression.
  • Cell shape is a critical factor influencing the functional outcomes of cytokine stimulation, such as cell proliferation.