Abstract
BackgroundMigration of T cells, including regulatory T (Treg) cells, into the secondary lymph organs is critically controlled by chemokines and adhesion molecules. However, the mechanisms by which Treg cells regulate organ-specific autoimmunity via these molecules remain unclear. Although we previously reported autoimmune exocrinopathy resembling Sjögren's syndrome (SS) in the lacrimal and salivary glands from C-C chemokine receptor 7 (CCR7)-deficient mice, it is still unclear whether CCR7 signaling might specifically affect the dynamics and functions of Treg cells in vivo. We therefore investigated the cellular mechanism for suppressive function of Treg cells via CCR7 in autoimmunity using mouse models and human samples.Methods and FindingsPatrolling Treg cells were detected in the exocrine organs such as lacrimal and salivary glands from normal mice that tend to be targets for autoimmunity while the Treg cells were almost undetectable in the exocrine glands of CCR7 −/− mice. In addition, we found the significantly increased retention of CD4+CD25+Foxp3+ Treg cells in the lymph nodes of CCR7 −/− mice with aging. Although Treg cell egress requires sphingosine 1-phosphate (S1P), chemotactic function to S1P of CCR7−/− Treg cells was impaired compared with that of WT Treg cells. Moreover, the in vivo suppression activity was remarkably diminished in CCR7 −/− Treg cells in the model where Treg cells were co-transferred with CCR7 −/− CD25-CD4+ T cells into Rag2 −/− mice. Finally, confocal analysis showed that CCR7+Treg cells were detectable in normal salivary glands while the number of CCR7+Treg cells was extremely decreased in the tissues from patients with Sjögren's syndrome.ConclusionsThese results indicate that CCR7 essentially governs the patrolling functions of Treg cells by controlling the traffic to the exocrine organs for protecting autoimmunity. Characterization of this cellular mechanism could have clinical implications by supporting development of new diagnosis or treatments for the organ-specific autoimmune diseases such as Sjögren's syndrome and clarifying how the local immune system regulates autoimmunity.
Highlights
Emerging evidence demonstrates that CD4+CD25+Foxp3+ regulatory T cells (Treg cells) play a central role in the protection of autoimmunity [1,2,3]
These results indicate that chemokine receptor 7 (CCR7) essentially governs the patrolling functions of Treg cells by controlling the traffic to the exocrine organs for protecting autoimmunity
It was demonstrated that the number of Treg cells increased in the lamina propria of inflamed tissues from patients with inflammatory bowel disease (IBD) while the number of Treg cells is significantly reduced in the peripheral blood mononuclear cells (PBMCs) from the patients [8,13,14]
Summary
Emerging evidence demonstrates that CD4+CD25+Foxp3+ regulatory T cells (Treg cells) play a central role in the protection of autoimmunity [1,2,3]. Treg cells actively suppress pathological and physiological immune responses, contributing to the maintenance of immunological self-tolerance and immune homeostasis. It has not been clarified whether the ability of Treg cells to migrate among tissues is important for them in exerting their suppressor function. In a model of type I diabetes, NOD mice, the disease resistance has been correlated with the expansion of Treg cells within inflamed pancreatic lymph nodes [12]. We previously reported autoimmune exocrinopathy resembling Sjogren’s syndrome (SS) in the lacrimal and salivary glands from C-C chemokine receptor 7 (CCR7)-deficient mice, it is still unclear whether CCR7 signaling might affect the dynamics and functions of Treg cells in vivo. We investigated the cellular mechanism for suppressive function of Treg cells via CCR7 in autoimmunity using mouse models and human samples
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