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Their Functional Status in Transplantation Levels of Foxp3 In Levels of Foxp3 in Regulatory T Cells Reflect Their Functional Status in Transplantation Sunil K. Chauhan, Daniel R. Saban, Hyung K. Lee and Reza Dana This information is current as of September 27, 2021. J Immunol 2009; 182:148-153; ; doi: 10.4049/jimmunol.182.1.148 http://www.jimmunol.org/content/182/1/148 Downloaded from References This article cites 25 articles, 7 of which you can access for free at: http://www.jimmunol.org/content/182/1/148.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 27, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Levels of Foxp3 in Regulatory T Cells Reflect Their Functional Status in Transplantation1 Sunil K. Chauhan,* Daniel R. Saban,* Hyung K. Lee,* and Reza Dana2*† Foxp3 expressing CD4؉CD25؉ regulatory T cells (Tregs) have been shown to prevent allograft rejection in clinical and animal models of transplantation. However, the role of Foxp3 in regulating Treg function, and the kinetics and mechanism of action of Tregs in inducing allograft tolerance in transplantation, are still not fully understood. Thus, we investigated the kinetics and function of Tregs in a mouse model of orthotopic corneal transplantation, the most common form of tissue grafting worldwide. In this study, using in vitro functional assays and in vivo Treg adoptive transfer assays, we show that far more relevant than Treg frequency is their level of Foxp3 expression, which is directly associated with the potential of Tregs to prevent allograft rejection by producing regulatory cytokines and suppressing effector T cell activation. In addition, our data clearly demonstrate that Tregs primarily suppress the induction of alloimmunity in regional draining lymph nodes rather than suppressing the Downloaded from effector phase of the immune response in the periphery. These findings provide new insights on Treg dynamics in trans- plantation, which are crucial for designing therapeutic strategies to modulate Treg function and to optimize Treg-based cell therapies for clinical translation. The Journal of Immunology, 2009, 182: 148–153. mmune-mediated rejection remains the single most important Foxp3 expression per se to analyze Treg function and the dynam- cause of graft failure in all forms of tissue transplantation. ics of Treg-mediated tolerance in transplantation may afford new http://www.jimmunol.org/ I However, spontaneous development of transplant tolerance opportunities to harness the potential of these cells to promote in some recipients indicates that, just as rejection is mediated by tolerance. active immune-mediated events, graft acceptance is also sustained We herein investigated the kinetics and function of Tregs in by active immunoregulatory mechanisms. One such immune allograft acceptors and rejectors using a well-characterized mouse mechanism is mediated by regulatory T cells (Tregs),3 that have model of corneal transplantation (18–20). In this model, ϳ50% of the capacity to suppress host immunity against transplants. Among allografts are rejected within 3 wk of transplantation while the the various forms of Tregs, CD4ϩCD25ϩ Tregs, which constitute remaining half enjoy indefinite survival, indicating involvement of 5–10% of CD4ϩ T cells, play a central role in inducing and main- active regulatory mechanisms that promote allograft longevity. taining tolerance to both self- and alloantigens (1–3). Compared with other transplant systems (e.g., skin, heart, kidney, by guest on September 27, 2021 Tregs are exemplified by their expression of transcription factor etc.) where a 100% graft rejection rate is observed in unmanipu- Foxp3 (4) and have been reported in a number of clinical and lated recipients, this model provides an exceptional opportunity to animal models of transplantation (5–8). Despite significant ad- study why some of the allografts are spontaneously accepted and vances in understanding Treg biology, several aspects relevant to to evaluate the role of Tregs in this high frequency of transplant transplant settings remain unclear. The majority of previous re- survival. ports have associated the outcome of the allograft primarily with In the present study, we clearly demonstrate that contrary to changes in the frequency of Tregs, either in the lymphoid com- previous reports the functional status of Tregs is more reflective of partment or at the graft site (9, 10). Moreover, levels of Foxp3 allograft outcome than their numbers. Moreover, the levels of expression have been interpreted primarily to reflect Treg fre- Foxp3 expression in Tregs are directly associated with their po- quency rather than defining the regulatory functions of these cells tential to suppress T cell activation and prevent allograft rejections. (11–15), although it has been shown that Foxp3 is critically im- portant for both the development of Tregs as well as their sup- Materials and Methods pressor function (16, 17). Thus, understanding the significance of Mice The 8- to 10-wk-old BALB/c (H-2d), C57BL/6 (H-2b), and C3H (H-2k) male mice were purchased from Taconic Farms (and used as recipients, *Schepens Eye Research Institute and †Department of Ophthalmology, Massachusetts donors, and third-party controls, respectively. The study was approved by Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114 the Institutional Animal Care and Use Committee, and the mice were Received for publication July 2, 2008. Accepted for publication October 29, 2008. treated according to the Association for Research in Vision and Ophthal- mology Statement for the Use of Animals in Ophthalmic and Vision The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance Research. with 18 U.S.C. Section 1734 solely to indicate this fact. Corneal transplantation 1 This work was supported by National Institutes of Health (NEI R01-12963) and the Eye Bank Association of America. Standard protocol for murine orthotopic corneal transplantation was used, 2 Address correspondence and reprint requests to Dr. Reza Dana, Schepens Eye Re- as described previously (18, 20). Briefly, donor center corneas (2-mm di- search Institute, 20 Staniford Street, Boston, MA 02114. E-mail address: ameter) were excised from C57BL/6 mice and sutured on to the recipient [email protected] graft beds prepared by excising a 1.5-mm site in the central cornea of 3 Abbreviations used in this paper: Treg, regulatory T cell; LN, lymph node; Teff, T BALB/c mice. Simultaneously, some BALB/c mice received syngeneic effector; MFI, mean fluorescence intensity. (BALB/c) grafts to control for the non-allospecific effects of surgery. The corneal sutures were removed 7 days after surgery. All grafts were eval- Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 uated using slit-lamp biomicroscopy at weekly intervals. Grafts were www.jimmunol.org The Journal of Immunology 149 defined as rejected when they became opaque and the iris details could not the draining LNs of recipients at 24 h posttransplantation (18). Allograft be recognized clearly using a standardized opacity grading (ranges, 0–5) survival rate in each group (n ϭ 6 per group) was monitored up to 8 wk scheme. This model renders an easy and confirmatory method to directly posttransplantation. evaluate graft endpoints in vivo at different time points without sacrificing the animals, which makes it an outstanding system to study immune re- Statistical analysis sponses in the transplant setting. Student’s t test was used for comparison of mean between the groups. Flow cytometry Kaplan-Meier analysis was adopted to construct survival curves, and the log-rank test was used to compare the rates of corneal graft survival. Data Ipsilateral draining submandibular and cervical lymph nodes (LNs) as well are presented as mean Ϯ SEM and considered significant at p Ͻ 0.05. as grafted corneas were harvested and single-cell suspensions were pre- pared. Single-cell suspensions of corneal samples were prepared by colla- Results genase digestion, as previously described (19). The isolated cells were Tregs in the draining LN express different levels of Foxp3 stained with the following Abs: Anti-CD4/CD3 FITC, anti-CD25 PE, and anti-FoxP3 PECy5 (eBioscience) and analyzed on an EPICS XL flow cy- Regional draining LN and grafted corneas were harvested from tometer (Beckman Coulter). graft recipients at weekly intervals up to wk 4 posttransplantation. Cell sorting At wk 3 posttransplantation, allograft recipients were separated into acceptors and rejectors. The flow cytometric analysis of drain- CD4ϩ T cells and CD4ϩCD25ϩ Tregs from the LN of naive and/or dif- ϩ ing LN cell suspensions showed no difference in the frequencies of ferent graft recipients were isolated by magnetic separation using CD4 T ϩ ϩ ϩ cell and Treg isolation kits (Miltenyi Biotec). Purity of sorted cells was CD4 CD25 Foxp3 Tregs, either as a proportion of the total ϩ Ͼ97%, and 95% of CD4ϩCD25ϩ Tregs were Foxp3ϩ in all the groups as CD4 T cells (range: 8.5–10.5%) or of the total LN cells (range: confirmed by flow cytometry. 4–5%) among syngeneic recipients, acceptors, and rejectors at any Downloaded from Real-time PCR of the time points (Fig.
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