Activated regulatory T cells are the major T cell type emigrating from the skin during a cutaneous immune response in mice

Tomura, Michio; Honda, Tetsuya; Tanizaki, Hideaki; Otsuka, Atsushi; Egawa, Gyohei; Tokura, Y.; Waldmann, Herman; Hori, Shohei; Cyster, Jason G.; Watanabe, Takeshi; Miyachi, Yoshiki; Kanagawa, Osami; Kabashima, Kenji

doi:10.1172/jci40926

Cited by 252 publications

(325 citation statements)

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“…To analyze the flux of cells into the insulitic lesion, we used a NOD backcross (>13 generations) of the Kaede tg mouse line, which allows noninvasive labeling and tracking of immunocytes in vivo (19)(20)(21)(22). In these mice, all cell types express the green fluorescent form of the Kaede protein, which can be irreversibly photoconverted into a red fluorescent form by violet light (29).…”

Section: Resultsmentioning

confidence: 99%

“…We used the Kaede/NOD transgenic (tg) mouse, which expresses ubiquitously the photoconvertible fluorescent protein Kaede (19)(20)(21)(22). We tracked cell movement from a known point of "labeling"-namely, s.c. lymph nodes (LNs), into the pancreas tissue itself, which allowed us to define the kinetics of entry for lymphoid and myeloid cells, much of which turned out to be independent of antigenic specificity.…”

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confidence: 99%

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Population dynamics of islet-infiltrating cells in autoimmune diabetes

Magnuson

Thurber

Köhler

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Type-1 diabetes in the nonobese diabetic (NOD) mouse starts with an insulitis stage, wherein a mixed population of leukocytes invades the pancreas, followed by overt diabetes once enough insulin-producing β-cells are destroyed by invading immunocytes. Little is known of the dynamics of lymphocyte movement into the pancreas during disease progression. We used the Kaede transgenic mouse, whose photoconvertible fluorescent reporter permits noninvasive labeling and subsequent tracking of immunocytes, to investigate pancreatic infiltrate dynamics and the requirement for antigen specificity during progression of autoimmune diabetes in the unmanipulated NOD mouse. Our results indicate that the insulitic lesion is very open with constant cell influx and active turnover, predominantly of B and T lymphocytes, but also CD11b + c + myeloid cells. Both naïve-and memory-phenotype lymphocytes trafficked to the insulitis, but Foxp3 + regulatory T cells circulated less than their conventional CD4 + counterparts. Receptor specificity for pancreatic antigens seemed irrelevant for this homing, because similar kinetics were observed in polyclonal and antigen-specific transgenic contexts. This "open" configuration was also observed after reversal of overt diabetes by anti-CD3 treatment. These results portray insulitis as a dynamic lesion at all stages of disease, continuously fed by a mixed influx of immunocytes, and thus susceptible to evolve over time in response to immunologic or environmental influences.Treg | cell tracer | reporter T ype-1 diabetes (T1D) is an organ-specific autoimmune disease initiated by a breakdown in T lymphocyte tolerance to islet-cell antigens; it comprises two stages: an occult phase of pancreatic inflammation, which reduces the number and function of insulin-producing β-cells and eventually provokes sufficient damage to result in the overt phase of diabetes, when insulin production is insufficient for proper glucose homeostasis. The genetics of T1D in mice and humans point primarily to a dysfunction of CD4 + T cells, because class II genes of the MHC, and several other loci that modify T-cell activation and regulation, are linked to T1D susceptibility (1).In nonobese diabetic (NOD) mice and other animal models (2), this initial inflammatory phase takes the form of insulitis, wherein a mixed population of leukocytes invades the islets of Langerhans. Insulitis starts around 3-4 wk of age and amplifies progressively until the onset of clinically overt diabetes (predominantly between 14 and 25 wk of age); it involves a wide array of cell types-T and B lymphocytes as well as myeloid cells-macrophages and dendritic cells (3), which can take on the organization of typical tertiary lymphoid structures (4). Importantly, insulitis variably affects different islets in a given animal, heavily infiltrated islets coexisting with fully intact and functional ones, even in advanced prediabetic mice.Inflammation in islets of human patients has been harder to evaluate, because access to material is obviously more difficult...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Population dynamics of islet-infiltrating cells in autoimmune diabetes

Magnuson

Thurber

Köhler

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…These altered kinetics suggested that inflammation during the second challenge was being limited by more active immune regulation. Given that Tregs have been shown to be capable of limiting CS responses (42)(43)(44), this raised the possibility that Tregs contribute to the accelerated resolution of inflammation during the second challenge. To understand the contribution of Tregs in this response, we therefore examined the time course of Treg accumulation in the two-challenge CS model.…”

Section: Infiltration Of Tregs Increases Progressively In Multiple Chmentioning

confidence: 99%

Endogenous Regulatory T Cells Adhere in Inflamed Dermal Vessels via ICAM-1: Association with Regulation of Effector Leukocyte Adhesion

Deane

Abeynaike

Norman

et al. 2012

The Journal of Immunology

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Regulatory T cells (Tregs) must express appropriate skin-homing adhesion molecules to exert suppressive effects on dermal inflammation. However, the mechanisms whereby they control local inflammation remain unclear. In this study we used confocal intravital microscopy in wild-type and Foxp3-GFP mice to examine adhesion of effector T cells and Tregs in dermal venules. These experiments examined a two-challenge model of contact sensitivity (CS) in which Treg abundance in the skin progressively increases during the course of the response. Adhesion of CD4+ T cells increased during CS, peaking 8–24 h after an initial hapten challenge, and within 4 h of a second challenge. At these time points, 40% of adherent CD4+ T cells were Foxp3+ Tregs. CD4+ T cell adhesion was highly dependent on ICAM-1, and consistent with this finding, anti–ICAM-1 prevented Treg adhesion. Skin TGF-β levels were elevated in skin during both challenges, in parallel with Treg adhesion. In the two-challenge CS model, inhibition of ICAM-1 eliminated Treg adhesion, an effect associated with a significant increase in neutrophil adhesion. Similarly, total CD4+ T cell depletion caused an increase in adhesion of CD8+ T cells. Because Treg adhesion was restricted by both of these treatments, these experiments suggest that adherent Tregs can control adhesion of proinflammatory leukocytes in vivo. Moreover, the critical role of ICAM-1 in Treg adhesion provides a potential explanation for the exacerbation of inflammation reported in some studies of ICAM-1–deficient mice.

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“…Murine contact hypersensitivity (CHS) is a frequently used animal models of ACD (2). Recent evidences show that Foxp3 + regulatory T cells (Tregs) play essential roles in the regulation of various immune responses including CHS (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

Generation of Helios reporter mice and an evaluation of the suppressive capacity of Helios⁺ regulatory T cells in vitro

Sugita

Hanakawa

Honda

et al. 2015

Experimental Dermatology

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Additional supporting data may be found in the supplementary information of this article.Appendix S1. Experimental design and supplementary references. Figure S1. Multipotency of mesenchymal stem cells (Yub637s cells). Figure S2. Enlarged view of Figure 2. Figure S3. Effect of CCL2 on stem cell proliferation. Figure S4. Effect of an inhibitor of CCR2 (RS102895) on stem cell migration enhanced by young HDF CM. Helios is a member of the Ikaros transcription factor family and has been reported to be a marker of thymus-derived regulatory T cells (Treg). Helios is an intracellular protein, however, and hence cannot be used as a marker to separate living Tregs. To solve this problem, we generated Helios reporter mice in which Helios+ cells selectively express Venus, a variant of green fluorescent protein. Most of the Tregs in the thymus expressed Helios, whereas its expression was varied in peripheral lymphoid organs. The Helios+ Treg-population was superior in ability to suppress both antigen-specific and TCR-stimulated T cell responses. We also showed that Helios+ Tregs inhibited the cytokine production by T cells more efficiently than Helios-Tregs. We conclude that Helios reporter mouse strain is a useful tool to study function of Helios and that Helios+ Tregs represent the highly suppressive population.

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Activated regulatory T cells are the major T cell type emigrating from the skin during a cutaneous immune response in mice

Cited by 252 publications

References 34 publications

Population dynamics of islet-infiltrating cells in autoimmune diabetes

Population dynamics of islet-infiltrating cells in autoimmune diabetes

Endogenous Regulatory T Cells Adhere in Inflamed Dermal Vessels via ICAM-1: Association with Regulation of Effector Leukocyte Adhesion

Generation of Helios reporter mice and an evaluation of the suppressive capacity of Helios⁺ regulatory T cells in vitro

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Activated regulatory T cells are the major T cell type emigrating from the skin during a cutaneous immune response in mice

Cited by 252 publications

References 34 publications

Population dynamics of islet-infiltrating cells in autoimmune diabetes

Population dynamics of islet-infiltrating cells in autoimmune diabetes

Endogenous Regulatory T Cells Adhere in Inflamed Dermal Vessels via ICAM-1: Association with Regulation of Effector Leukocyte Adhesion

Generation of Helios reporter mice and an evaluation of the suppressive capacity of Helios+ regulatory T cells in vitro

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Generation of Helios reporter mice and an evaluation of the suppressive capacity of Helios⁺ regulatory T cells in vitro