Cofilin activation in peripheral CD4 T cells of HIV-1 infected patients: a pilot study
© Wu et al; licensee BioMed Central Ltd. 2008
Received: 09 September 2008
Accepted: 17 October 2008
Published: 17 October 2008
Cofilin is an actin-depolymerizing factor that regulates actin dynamics critical for T cell migration and T cell activation. In unstimulated resting CD4 T cells, cofilin exists largely as a phosphorylated inactive form. Previously, we demonstrated that during HIV-1 infection of resting CD4 T cells, the viral envelope-CXCR4 signaling activates cofilin to overcome the static cortical actin restriction. In this pilot study, we have extended this in vitro observation and examined cofilin phosphorylation in resting CD4 T cells purified from the peripheral blood of HIV-1-infected patients. Here, we report that the resting T cells from infected patients carry significantly higher levels of active cofilin, suggesting that these resting cells have been primed in vivo in cofilin activity to facilitate HIV-1 infection. HIV-1-mediated aberrant activation of cofilin may also lead to abnormalities in T cell migration and activation that could contribute to viral pathogenesis.
Cofilin is a member of the actin-depolymerizing factor (ADF) family of proteins  that play a central role in regulating actin dynamics [2, 3]. The actin-severing and depolymerization activities of cofilin are essential in controlling cell polarity , cell motility  and cell division [6, 7]. In the human immune system, cofilin has also been implicated in two hallmark activities of T cells, namely chemotaxis and T cell activation . In chemotaxis, directed cell movement towards chemoattractants is controlled by localized cortical actin polymerization and depolymerization, and cofilin is the driving force for promoting the cortical actin dynamics . In antigen-specific T cell activation the reorganization of the cortical actin plays a critical role in the formation of the immunological synapse. Engagement of CD2 or CD28 receptors but not TCR results in cofilin activation and its association with the actin cytoskeleton . Peptides that block cofilin binding to actin result in severe defects in T cell activation .
Cofilin activity is regulated through phosphorylation and dephosphorylation at serine-3 by the simultaneous actions of cofilin kinases and phosphatases [12–14]. Phosphorylated cofilin is unable to bind to F-actin; thus cofilin is inactivated by phosphorylation and activated by dephosphorylation [13, 14]. The direct upstream kinases that inactivate cofilin are the LIM kinases (LIMK1 and LIMK2) [15, 16], whereas several serine phosphatases such as slingshot, chronophin [17, 18], PP1α and PP2A  dephosphorylate and activate cofilin.
Recently, we  and others  have demonstrated that in unstimulated resting CD4 T cells purified from the peripheral blood, cofilin exists largely as the phosphorylated form, implying that in the absence of chemotactic stimulation or T cell activation, cofilin is largely inactive. We have also suggested that this restricted cofilin activity in resting T cells inhibits the cortical actin dynamics, hindering viral post-entry migration. Thus, HIV-1 hijacks chemokine receptor signalling through CXCR4 to trigger the activation of cofilin. This process increases the cortical actin dynamics, facilitating viral nuclear migration [20, 22].
HIV-1-mediated aberrant activation of cofilin in resting CD4 T cells may affect normal T cell migration and T cell activation. In the human immune system, cofilin is directly involved in chemotaxis and T cell activation. For example, cofilin was shown to affect SDF1α-driven T cell chemotaxis, and blocking cofilin phosphorylation diminishes actin reorganization and normal chemotactic response . During T cell activation, cofilin is activated by co-stimulation signals to mediate cortical actin reorganization, which plays a critical role in the formation and stabilization of the immunological synapse. It is commonly known that genetic defects affecting actin activity by means of a deficiency in signaling molecules, such as WASP, cause immunodeficiency [31, 32]. It would not be a surprise if cofilin dysregulation also results in T cell-mediated immunodeficiencies, given the central role of cofilin in regulating actin dynamics in T cells .
The demonstration of cofilin activation in resting CD4 T cells of HIV-1-infected patients offers new avenues for investigation into viral pathogenesis. It has long been recognized that the residual CD4 T cells in HIV-1-infected patients have numerous functional abnormalities, such as loss of T helper function , T cell anergy [35, 36], increased T cell proliferation  and abnormal T cell homing and migration [38, 39]. These T cell defects largely result from a bystander effect . It remains to be determined whether some of these abnormalities are directly linked to aberrant activation of cofilin in resting CD4 T cells. Additionally, as shown in this pilot study, the peripheral CD4 T cells in HIV-1 patients strikingly resemble the migratory T lymphoma cells in terms of carrying active cofilin [21, 41]. It is likely that these CD4 T cells also have abnormal migratory behaviours associated with aberrant cofilin activation. It remains unknown whether migratory abnormalities could contribute to the eventual destruction of T cells in lymph nodes or tissues. Finally, the identification of cofilin as a critical molecule in resting CD4 T cells of infected patients may serve as a diagnostic marker to reflect alterations of T cell function in disease progression.
LIM Domain Kinase 1
T Cell Receptor
Highly Active Antiretroviral Therapy
Nonequilibrium pH Gel Electrophoresis
Human Leukocyte Antigen-DR
Wiskott-Aldrich Syndrome Protein
Stromal-Cell-Derived Factor 1α.
We thank the George Mason University (GMU) Student Health Center and the GMU and Chesapeake Bay Institutional Review Boards. AY was supported by the National Defense Science and Engineering Fellowship. This work was supported by GMU and by Public Health Service grant AI069981 from NIAID to YW.
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