The calcium feedback loop and T cell activation: How cytoskeleton networks control intracellular calcium flux

Noah Joseph, Barak Reicher, Mira Barda-Saad

Research output: Contribution to journalReview articlepeer-review

103 Scopus citations


During T cell activation, the engagement of a T cell with an antigen-presenting cell (APC) results in rapid cytoskeletal rearrangements and a dramatic increase of intracellular calcium (Ca2 +) concentration, downstream to T cell antigen receptor (TCR) ligation. These events facilitate the organization of an immunological synapse (IS), which supports the redistribution of receptors, signaling molecules and organelles towards the T cell-APC interface to induce downstream signaling events, ultimately supporting T cell effector functions. Thus, Ca2 + signaling and cytoskeleton rearrangements are essential for T cell activation and T cell-dependent immune response. Rapid release of Ca2 + from intracellular stores, e.g. the endoplasmic reticulum (ER), triggers the opening of Ca2 + release-activated Ca2 + (CRAC) channels, residing in the plasma membrane. These channels facilitate a sustained influx of extracellular Ca 2 + across the plasma membrane in a process termed store-operated Ca2 + entry (SOCE). Because CRAC channels are themselves inhibited by Ca2 + ions, additional factors are suggested to enable the sustained Ca2 + influx required for T cell function. Among these factors, we focus here on the contribution of the actin and microtubule cytoskeleton. The TCR-mediated increase in intracellular Ca2 + evokes a rapid cytoskeleton-dependent polarization, which involves actin cytoskeleton rearrangements and microtubule-organizing center (MTOC) reorientation. Here, we review the molecular mechanisms of Ca2 + flux and cytoskeletal rearrangements, and further describe the way by which the cytoskeletal networks feedback to Ca2 + signaling by controlling the spatial and temporal distribution of Ca2 + sources and sinks, modulating TCR-dependent Ca2 + signals, which are required for an appropriate T cell response. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Hervé.

Original languageEnglish
Pages (from-to)557-568
Number of pages12
JournalBiochimica et Biophysica Acta - Biomembranes
Issue number2
StatePublished - Feb 2014

Bibliographical note

Funding Information:
The authors thank Dr. Alex Braiman for critical reading of the manuscript. MBS thanks the following agencies for their research support: The Israel Science Foundation for grant nos. 1659/08 , 971/08 , 1503/08 and 491/10 , the Ministries of Health & Science for grant nos. 3-4114 and 3-6540 , the Israel Cancer Association through the Estate of the late Alexander Smidoda, and the Taubenblatt Family Foundation for a Bio-medicine grant for excellence.


  • Actin polymerization
  • Calcium
  • Cytoskeleton
  • Lymphocyte
  • Signaling
  • TCR


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