Role of Dynamic Actin Cytoskeleton Remodeling in Foxp3 Regulatory T Cell Development and Function: Implications for Osteoclastogenesis.

In T cells, processes such as migration and immunological synapse formation are accompanied by the dynamic reorganization of the actin cytoskeleton, which has been suggested to be mediated by regulators of RhoGTPases and by F-actin bundlers. SWAP-70 controls F-actin dynamics in various immune cells, but its role in T cell development and function has remained incompletely understood. CD4 regulatory T (Treg) cells expressing the transcription factor Foxp3 employ diverse mechanisms to suppress innate and adaptive immunity, which is critical for maintaining immune homeostasis and self-tolerance. Here, we propose as a novel member of the Foxp3-dependent canonical Treg cell signature. We show that mice have increased numbers of Foxp3 Treg cells with an effector/memory-like phenotype that exhibit impaired suppressor function , but maintain overall immune homeostasis . Upon formation of an immunological synapse with antigen presenting cells , cytosolic SWAP-70 protein is selectively recruited to the interface in Treg cells. In this context, Treg cells fail to downregulate CD80/CD86 on osteoclast precursor cells by trans-endocytosis and to efficiently suppress osteoclastogenesis and osteoclast function. These data provide first evidence for a crucial role of SWAP-70 in Treg cell biology and further highlight the important non-immune function of Foxp3 Treg cells in bone homeostasis mediated through direct SWAP-70-dependent mechanisms.