Abstract
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 Swap-70 as a novel member of the Foxp3-dependent canonical Treg cell signature. We show that Swap-70-/- mice have increased numbers of Foxp3+ Treg cells with an effector/memory-like phenotype that exhibit impaired suppressor function in vitro, but maintain overall immune homeostasis in vivo. Upon formation of an immunological synapse with antigen presenting cells in vitro, cytosolic SWAP-70 protein is selectively recruited to the interface in Treg cells. In this context, Swap-70-/- 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.
Highlights
Foxp3+ regulatory T (Treg) cells are indispensable for the maintenance of immunological selftolerance and homeostasis
Il2ra mRNA was constitutively expressed in naïve and memory-type Treg cells and up-regulated in CD4+ Tcon upon short-term stimulation, while Foxp3 expression was restricted to Treg cells (Figure 1A left, middle)
Since SWAP-70 modulates F-actin rearrangements, regulates integrin activity, and cell migration and adhesion in a variety of cells of hematopoietic origin [26, 28–31, 33, 35], it seems tempting to speculate that the selective constitutive expression of SWAP-70 in the Foxp3+ Treg cell subset of the CD4+ T cell lineage [37] might represent a direct consequence of Foxp3-dependent transcriptional regulation and that SWAP-70 participates in the regulation of actin dynamics in Treg cells
Summary
Foxp3+ regulatory T (Treg) cells are indispensable for the maintenance of immunological selftolerance and homeostasis. Since osteoclasts are derived from hematopoietic precursors, express a variety of immune receptors and are regulated to dendritic cells (DCs) and macrophages, it has been proposed, that osteoclasts play a role in the active regulation of the immune system and can act for example as antigen presenting cells (APCs) [19–21]. In this context, it was suggested that, similar to DCs, osteoclast progenitors express on their surface the costimulatory molecules CD80 and CD86, and that Treg cells can control osteoclastogenesis via engagement of CD80/CD86 by CTLA-4 [9, 22]
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