Abstract
Cofilin is an essential actin remodeling protein promoting depolymerization and severing of actin filaments. To address the relevance of cofilin for the development and function of T cells in vivo, we generated knock-in mice in which T-cell–specific nonfunctional (nf) cofilin was expressed instead of wild-type (WT) cofilin. Nf cofilin mice lacked peripheral αβ T cells and showed a severe thymus atrophy. This was caused by an early developmental arrest of thymocytes at the double negative (DN) stage. Importantly, even though DN thymocytes expressed the TCRβ chain intracellularly, they completely lacked TCRβ surface expression. In contrast, nf cofilin mice possessed normal numbers of γδ T cells. Their functionality was confirmed in the γδ T-cell–driven, imiquimod (IMQ)-induced, psoriasis-like murine model. Overall, this study not only highlights the importance of cofilin for early αβ T-cell development but also shows for the first time that an actin-binding protein is differentially involved in αβ versus γδ T-cell development.
Highlights
One requirement for T-cell–mediated immune surveillance is the permanent reshaping of the cell body
To move through the body and to fulfill their specific functions, T cells need to dynamically reshape their cell body. This requires remodeling the actin cytoskeleton using a plethora of actin-binding proteins, including cofilin
Whereas the majority of T cells use one type of cell membrane protein called αβ T cell receptor (TCR) to recognize their target, a minor population of T cells use a different type of receptors that are called γδTCR
Summary
One requirement for T-cell–mediated immune surveillance is the permanent reshaping of the cell body. Dephosphorylated cofilin can translocate to the nucleus where it may have anti-apoptotic functions and may enhance transcription [11,18] It can serve as nuclear shuttle for actin [11,19], which is involved in different nuclear mechanisms (reviewed by Falahzadeh and colleagues [20]). Besides T-cell costimulation, chemokine receptor triggering (e.g., by SDF-1α) can lead to the dephosphorylation of cofilin [21] In this regard, it was shown that an active mitogen-activated protein kinase kinase (MEK) cofilin module is needed for T-cell movement [21], known to be driven by constant actin flow, i.e. migration in 3D environments [22,23,24,25]. Even PIP2-bound cofilin becomes active, leading to enhanced actin dynamics in the vicinity of the plasma membrane [28]
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