Naïve CD4⁺ DO11.10 TCR⁺ T cells from coronin 1^+/+ and coronin 1^-/- mice were either stimulated with chemokine (CCL19, 20 min) (a,b) or conjugated with OVA-peptide (323-339) pulsed A20 cells for 20 min (c,d). While wildtype naive T cells are able to polarize F-actin and form a uropod in response to CCL19, coronin 1^-/- naive T cells demonstrate non-focal polarization of F-actin. In contrast, naive T cells form normal contacts with antigen presenting cells independent of the presence or absence of coronin 1. Following stimulation the cells were fixed, permeabilized and stained for F-actin (phalloidin). Samples were analyzed by deconvolution microscopy (DeltaVision RT, Applied Precision, LLC, Issaquah, WA).

The assembly and branching of actin filaments is primarily controlled by the Arp2/3 complex. Coronin is a natural antagonist of Arp2/3 that has been implicated in intracellular membrane transport and motility in both yeast and amoeba. In a study published in Science, Andrew Chan and colleagues now provide insights into the function of mammalian coronin in vivo.

To examine the physiological role of coronin, the authors generated coronin 1^-/- mice. Although they do not exhibit any gross developmental abnormalities, these mice have a reduced number of peripheral T cells. The authors show that chemokine-induced migration of CD4⁺ coronin 1^-/- thymocytes is reduced compared to wild-type cells in both whole-organ thymic cultures and in vivo thymic egress. Adoptive transfer experiments in which purified CD4⁺ thymocytes from coronin 1^-/- or control mice were differentially labeled and injected into recipient mice, further demonstrate that coronin 1 is required for T-cell homing to secondary lymphocyte organs.

Coronin 1^-/- T cells also fail to polarize after stimulation with the chemokine CCL19, which normally leads to an accumulation of talin at the leading edge and the extension of a uropod at the trailing end. Furthermore, despite having higher basal levels of F-actin, CCL19 was unable to induce further actin polymerization in coronin 1-deficient cells. These cytoskeletal defects were associated with defective stromal cell-derived factor-1 (SDF1)-mediated activation of Rac, a key stimulator of actin assembly.

Although coronin 1 is required for T-cell homing, it does not seem to be required for immunological-synapse formation or T-cell activation. However, the authors found that coronin 1 has an important role in cell survival. In the absence of coronin 1, increased rates of T-cell apoptosis were observed both in vitro and in vivo. As actin dynamics have been linked with mitochondrial membrane potential (MMP) in yeast, the authors examined the effect of coronin 1 on actin polymerization and apoptosis. They found that the interaction between coronin 1 and Arp2/3 increases actin assembly and leads to a loss of MMP which in turn, causes cell death. These effects were partially reversed by the actin depolymerizing agent latrunculin.

Together, the results of this study demonstrate a role for coronin 1 in lymphocyte homing, and in the regulation of MMP and cell viability through the regulation of actin dynamics. Potentially, actin dynamics could modulate MMP by regulating voltage dependent channels on mitochondria or by delivering pro-apoptotic proteins to them. Future studies on this intriguing issue will be eagerly awaited.

Author: Monica Hoyos-Flight