Research Article: In Situ Patrolling of Regulatory T Cells Is Essential for Protecting Autoimmune Exocrinopathy

Date Published: January 5, 2010

Publisher: Public Library of Science

Author(s): Naozumi Ishimaru, Takeshi Nitta, Rieko Arakaki, Akiko Yamada, Martin Lipp, Yousuke Takahama, Yoshio Hayashi, Derya Unutmaz.

Abstract: Migration 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.

Partial Text: Emerging evidence demonstrates that CD4+CD25+Foxp3+ regulatory T cells (Treg cells) play a central role in the protection of autoimmunity [1]–[3]. Treg cells actively suppress pathological and physiological immune responses, contributing to the maintenance of immunological self-tolerance and immune homeostasis. However, it has not been clarified whether the ability of Treg cells to migrate among tissues is important for them in exerting their suppressor function. On the other hand, recent reports showed that Treg cells are also present within non-lymphoid sites in the periphery, including autoimmune lesions, infectious sites, and tumors [4]. The depletion of Treg cells from normal mice leads to spontaneous development of various autoimmune diseases, such as autoimmune thyroiditis, type 1 diabetes, gastritis, and inflammatory bowel disease [5]–[8]. Although the injection of Treg cells into animal models for autoimmunity can prevent or reduce the onset of diseases [9]–[11], it is still unclear which sites of Treg cells can display their function in vivo. 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]. Moreover, 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]. Although various molecular and cellular events have been described to explain the mechanisms of Treg-mediated suppression [15], [16], none of the proposed mechanisms can explain all aspects of in vivo suppression.

Our previous report demonstrated that CCR7 plays an essential role in the migration of thymocytes from the cortex to the medulla in the thymus for maintaining central immune tolerance [26]. It was suggested that mature thymocytes exported from the cortex in the absence of CCR7 were potent in causing autoimmunity. We found that the autoreactive T cells inducing autoimmune lesions in CCR7−/− mice are generated in the thymus where positively selected thymocytes including any autoreactive T cells are exported from the cortex. However, it is still unclear how the autoimmunity is caused by the disturbance in the peripheral immune system.



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