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And Sialoadenitis Mice to Suppress Lupus Glomerulonephritis T Cells Failure of CD25+ T Cells from Lupus-Prone Mice to Suppress Lupus Glomerulonephritis and Sialoadenitis This information is current as Harini Bagavant and Kenneth S. K. Tung of September 28, 2021. J Immunol 2005; 175:944-950; ; doi: 10.4049/jimmunol.175.2.944 http://www.jimmunol.org/content/175/2/944 Downloaded from References This article cites 29 articles, 12 of which you can access for free at: http://www.jimmunol.org/content/175/2/944.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 28, 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 © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Failure of CD25؉ T Cells from Lupus-Prone Mice to Suppress Lupus Glomerulonephritis and Sialoadenitis1 Harini Bagavant2 and Kenneth S. K. Tung The development of organ-specific autoimmune diseases in mice thymectomized on day 3 of life (d3tx mice) can be prevented by transferring CD4؉CD25؉ T cells from syngeneic, normal adult mice. Using a d3tx model, we asked whether CD4؉CD25؉ T cell deficiency contributes to glomerulonephritis (GN) in lupus-prone mice. New Zealand Mixed 2328 (NZM2328) mice spontaneously develop autoantibodies to dsDNA and female-dominant, fatal GN. After d3tx, both male and female NZM2328 mice developed 1) accelerated dsDNA autoantibody response, 2) early onset and severe proliferative GN with massive mesangial immune complexes, and 3) autoimmune disease of the thyroid, lacrimal gland, and salivary gland. The d3tx male mice also developed autoimmune prostatitis. -The transfer of CD25؉ cells from 6-wk-old asymptomatic NZM2328 donors effectively suppressed dsDNA autoantibody and the de velopment of autoimmune diseases, with the exception of proliferative lupus GN and sialoadenitis. This finding indicates that NZM2328 Downloaded from lupus mice have a selective deficiency in T cells that regulates the development of lupus GN and sialoadenitis. After d3tx, the proliferative GN of female mice progressed to fatal GN, but largely regressed in the male, thereby revealing a checkpoint in lupus GN progression that depends on gender. The Journal of Immunology, 2005, 175: 944–950. he CD4ϩCD25ϩ regulatory T cell (Treg)3 subset has been SLE is a complex multisystemic autoimmune disease, charac- established as a powerful regulator of the host immune terized by circulating Ab to nuclear and cytoplasmic Ags (9). Lu- http://www.jimmunol.org/ T response to foreign and self Ags (1, 2). Adoptive transfer pus glomerulonephritis (GN) affects ϳ50% of lupus patients and is of Treg cells from a normal host silences the autoreactive T cell associated with the deposition of immune complexes and comple- response and prevents or abrogates autoimmune disease develop- ment components in the glomeruli, with infiltration of inflamma- ment. Study of the spontaneous fatal human immune dysregula- tory cells and, in severe disease, glomerular and interstitial fibrosis, tion, polyendocrinopathy, enteropathy, X-linked syndrome, and tubular atrophy, and renal failure (10). The lupus-prone New Zea- the fatal lymphoproliferative disorder in scurfy mice has provided land Mixed 2328 (NZM2328) mouse, a recombinant inbred strain compelling evidence that autoimmune disease can result from that originated from the crosses among New Zealand Black and functional mutations of the forkhead/winged helix transcription New Zealand White mice and their progenies also develops GN factor, which is essential for Treg development and function (3–5). (11). NZM2328 mice have autoantibodies to nuclear Ags including by guest on September 28, 2021 This exciting finding begs the question of whether deficiency in dsDNA. At 12 mo of age, 72% of females and 25% of males Treg cells also contributes to the pathogenesis of the more com- develop severe proteinuria with lupus GN (12). mon human autoimmune diseases, such as systemic lupus ery- Previous studies have explored the presence of Treg cells for the thematosus (SLE), multiple sclerosis, and rheumatoid arthritis. In- dsDNA autoantibody response. Seo et al. (13) showed that the deed, recent studies have described a deficiency of in vitro transfer of Treg cells into mice expressing anti-dsDNA BCRs ab- ϩ ϩ CD4 CD25 T cell function in patients with multiple sclerosis rogated the maturation process of transgenic B cells into Ab-form- ϩ and rheumatoid arthritis (6, 7). Reduced numbers of CD25 T ing cells. La Cava et al. (14) showed that Treg cells from (New ϫ cells in the peripheral blood of SLE patients have also been re- Zealand Black New Zealand White) F1 mice injected with a ported (8). However, the clinical studies are not able to evaluate tolerogenic peptide from the CDR3 region of an anti-dsDNA Ab the disease-suppressing capacity of Treg cells in vivo. We there- prevented B cell synthesis of dsDNA Ab. In these studies the ques- fore turned to murine models of SLE to determine whether Treg tion of whether CD25ϩ regulatory T cells can suppress lupus GN cells in these mice are deficient in their capacity to inhibit spon- was not investigated. taneous systemic autoimmune disease. In the present study we used the classical approach to induce autoimmune disease by thymectomy (tx) on day 3 of life (d3tx) (15, 16). Although the mechanism of d3tx-induced autoimmune Department of Pathology and University of Virginia Specialized Center of Research diseases is not fully understood, the current belief is that d3tx on Systemic Lupus Erythematosus, University of Virginia, Charlottesville, VA 22908 results in preferential depletion of CD4ϩCD25ϩ Treg cells relative Received for publication March 18, 2005. Accepted for publication May 13, 2005. to the autoreactive CD25Ϫ T effector population. The resultant The costs of publication of this article were defrayed in part by the payment of page state of regulatory and effector T cell imbalance is also exagger- charges. This article must therefore be hereby marked advertisement in accordance ated by homeostatic T cell expansion in the profoundly lym- with 18 U.S.C. Section 1734 solely to indicate this fact. phopenic d3tx mice (17, 18). Regardless of the precise mechanism 1 This work was supported by National Institutes of Health Grants R01AI41236, AR45222, and K01DK063065. of disease induction, all d3tx-induced, organ-specific autoimmune 2 diseases in nonlupus mice are readily prevented by early infusion Address correspondence and reprint requests to Dr. Harini Bagavant, Division of ϩ ϩ Rheumatology, Department of Internal Medicine, Health Sciences Center, Box of CD4 CD25 T cells from normal syngeneic adults (19, 20). 800412, University of Virginia, Charlottesville, VA 22908. E-mail address: In this study we have investigated the capacity of CD25ϩ reg- [email protected] ulatory T cells from lupus-prone NZM2328 mice to suppress au- 3 Abbreviations used in this paper: Treg cell, CD25ϩ regulatory T cell; d3tx, tx on day 3 of life; GN, glomerulonephritis; NZM, New Zealand Mixed; tx, thymectomy; SLE, toimmune disease and autoantibody response in d3tx NZM2328 systemic lupus erythematosus; tx, thymectomy, thymectomized. lupus mice. The study was possible because of the observation, Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 The Journal of Immunology 945 described below, that d3tx NZM2328 mice developed severe pro- mounting fluid (Vector Laboratories), and fluorescence intensity was liferative GN of early onset, sialoadenitis, and accelerated autoan- graded from 0 to 4 in a blinded fashion. tibody response to dsDNA. As an important control, we studied the Acid elution of Igs from kidney capacity of the same population of CD25ϩ T cells from NZM2328 mice to suppress other organ-specific autoimmune diseases unre- Igs were eluted from the kidney as previously described (23). Briefly, each individual frozen kidney was weighed and homogenized in cold PBS on lated to the lupus syndrome. ice. The homogenate was centrifuged at 1200 ϫ g for 10 min at 4°C. The pellets were washed by resuspension in cold PBS, followed by vortexing Materials and Methods and centrifugation to remove serum proteins. The washing was repeated Ͻ Mice until the OD280 of the supernatant was 0.05. The pellet was then sus- pended in 0.1 M glycine with 1% BSA, pH 2.8 (10 ml/g kidney), and A colony of NZM2328 has been maintained and housed under specific mixed gently at 4°C for 20 min. The suspension was centrifuged, and pathogen-free conditions at the University of Virginia Animal care facility. supernatant was immediately neutralized with 1 M Tris base. All mice used were generated in this facility. The animal housing and ϩ Ϫ experimental protocols were performed in accordance with National Insti- Purification of CD25 and CD25 T cells tutes of Health guidelines. Male and female NZM2328 mice were thymec- Lymph nodes were harvested from NZM2328 mice and enriched for T tomized (tx) on days 2–4 after birth using established protocols and aseptic cells by negative selection on T cell enrichment columns (R&D Systems). technique (21). Briefly, 2- to 4-day-old mice were anesthetized using hy- The cells were incubated with biotinylated 7D4 Ab to CD25 (BD Pharm- pothermia, and the sternum was exposed through a midline incision. The ingen). After washing, the cells were incubated with streptavidin-PE sternum and ribs were cut, and the thymus was aspirated using a Pasteur (Rockland), followed by anti-PE magnetic beads (Miltenyi Biotec).
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