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Review
. 2013 Nov;256(1):30-47.
doi: 10.1111/imr.12115.

Cofilin: A Redox Sensitive Mediator of Actin Dynamics During T-cell Activation and Migration

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Free PMC article
Review

Cofilin: A Redox Sensitive Mediator of Actin Dynamics During T-cell Activation and Migration

Yvonne Samstag et al. Immunol Rev. .
Free PMC article

Erratum in

  • Immunol Rev. 2015 Mar;264(1):382

Abstract

Cofilin is an actin-binding protein that depolymerizes and/or severs actin filaments. This dual function of cofilin makes it one of the major regulators of actin dynamics important for T-cell activation and migration. The activity of cofilin is spatio-temporally regulated. Its main control mechanisms comprise a molecular toolbox of phospho-, phospholipid, and redox regulation. Phosphorylated cofilin is inactive and represents the dominant cofilin fraction in the cytoplasm of resting human T cells. A fraction of dephosphorylated cofilin is kept inactive at the plasma membrane by binding to phosphatidylinositol 4,5-bisphosphate. Costimulation via the T-cell receptor/CD3 complex (signal 1) together with accessory receptors (signal 2) or triggering through the chemokine SDF1α (stromal cell-derived factor 1α) induce Ras-dependent dephosphorylation of cofilin, which is important for immune synapse formation, T-cell activation, and T-cell migration. Recently, it became evident that cofilin is also highly sensitive for microenvironmental changes, particularly for alterations in the redox milieu. Cofilin is inactivated by oxidation, provoking T-cell hyporesponsiveness or necrotic-like programmed cell death. In contrast, in a reducing environment, even phosphatidylinositol 4,5-bisphosphate-bound cofilin becomes active, leading to actin dynamics in the vicinity of the plasma membrane. In addition to the well-established three signals for T-cell activation, this microenvironmental control of cofilin delivers a modulating signal for T-cell-dependent immune reactions. This fourth modulating signal highly impacts both initial T-cell activation and the effector phase of T-cell-mediated immune responses.

Keywords: T-cell activation; actin cytoskeleton; costimulation; immune synapse; microenvironment; redox.

Figures

Figure 1
Figure 1
Structures and regulation of the actin cytoskeleton. (A) F-actin was stained in COS-7 cells with phalloidin (AlexaFluor-488) and acquired with structured-illumination microscopy (3D-SIM acquired in the SBIC-Nikon Imaging Centre at Biopolis, Heidelberg, Germany). The most dynamic actin reorganization takes place at the migratory front, although actin dynamics are important throughout the whole cell. F-actin bundling or crosslinking mediates elasticity. (B) Actin polymerization, dynamics, and elasticity. Key proteins for each step are depicted (reviewed in –5). Arp2/3, actin-related protein 2/3; NPFs, nucleation-promoting factors.
Figure 2
Figure 2
Regulation sites of cofilin. Cofilin is a highly regulated protein. The figure displays a threefold regulation of cofilin: phospho-regulation at serine 3, redox regulation at cysteine residues, and phospholipid regulation via PI(4,5)P2 binding.
Figure 3
Figure 3
Cofilin is required for organized receptor clustering in the immune synapse. Upper part: Contact zone between APCs and T cells. Lower part: En face view of the bull's-eye shaped organization of the SMACs in the T-cell membrane. Cofilin localizes to the pSMAC and dSMAC. Immune synapses have been comprehensively reviewed ,.
Figure 4
Figure 4
Spatio-temporal and microenvironmental control of cofilin in T cells. Costimulation induces cofilin activation via Ras (A1), which results in cofilin dephosphorylation in the cytoplasm, and via PLC (A2), which liberates dephosphorylated cofilin from PI(4,5)P2 inhibition. This results in the onset of activation-induced actin dynamics (B). In addition to its functions for actin dynamics, dephosphorylated cofilin can carry actin into the nucleus (C). Thereby, it can modulate gene transcription by altering the nuclear actin pool and the activity of RNA polymerase II. PI(4,5)P2 bound cofilin is inactive and detains F-actin at the plasma membrane (= cortical actin, D). In the presence of a reducing milieu, this cofilin pool gets active despite binding to PI(4,5)P2. Thereby, actin dynamics near the plasma membrane are enhanced (E). In contrast, a strong pro-oxidative milieu can oxidize (inactivate) cofilin which results in a stiff actin cytoskeleton and T-cell hyporesponsiveness or even necrotic-like programmed cell death (NL-PCD) through mitochondrial disintegration (F).
Figure 5
Figure 5
The ‘four signal model of T-cell activation’. T-cell costimulation via the TCR/CD3 complex (competence or first signal) and costimulatory receptors (progression or second signal) is mandatory to induce cofilin dephosphorylation and full T-cell activation. Neither the first nor second signal alone is sufficient to provoke cofilin and T-cell activation. The third signal mediates T-cell differentiation via cytokines like IL-12. Effects on cofilin are as yet unknown. A fourth signal is provided by the microenvironment. This fourth signal has a modulating function that adapts T-cell responses to the conditions in the surrounding tissue. It can be activating (e.g. reducing milieu) or inhibiting (e.g. oxidative milieu or arginine deprivation).

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References

    1. Angus KL, Griffiths GM. Cell polarisation and the immunological synapse. Curr Opin Cell Biol. 2013;25:85–91. - PMC - PubMed
    1. Burkhardt JK, Carrizosa E, Shaffer MH. The actin cytoskeleton in T cell activation. Annu Rev Immunol. 2008;26:233–259. - PubMed
    1. Babich A, Li S, O'Connor RS, Milone MC, Freedman BD, Burkhardt JK. F-actin polymerization and retrograde flow drive sustained PLCgamma1 signaling during T cell activation. J Cell Biol. 2012;197:775–787. - PMC - PubMed
    1. Piragyte I, Jun CD. Actin engine in immunological synapse. Immune Netw. 2012;12:71–83. - PMC - PubMed
    1. Samstag Y, Eibert SM, Klemke M, Wabnitz GH. Actin cytoskeletal dynamics in T lymphocyte activation and migration. J Leukoc Biol. 2003;73:30–48. - PubMed
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