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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0901773v1 183/10/6346    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Zhang, L. Articles by Datta, S. K. PubMed PubMed Citation Articles by Zhang, L. Articles by Datta, S. K.

Regulatory T Cell (Treg) Subsets Return in Patients with Refractory Lupus following Stem Cell Transplantation, and TGF-β-Producing CD8⁺ Treg Cells Are Associated with Immunological Remission of Lupus¹

Li Zhang,^* Anne M. Bertucci,^* Rosalind Ramsey-Goldman,^* Richard K. Burt, and Syamal K. Datta^2*

^*Division of Rheumatology and Division of Immunotherapy, Department of Medicine, and Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611

Compared with conventional drug therapy, autologous hemopoietic stem cell transplantation (HSCT) can induce very-long-term remission in refractory lupus patients. Herein, we show that in posttransplant patients, both CD4⁺CD25^highFoxP3⁺ and an unusual CD8⁺FoxP3⁺ Treg subset return to levels seen in normal subjects; accompanied by almost complete inhibition of pathogenic T cell response to critical peptide autoepitopes from histones in nucleosomes, the major lupus autoantigen from apoptotic cells. In addition to a stably sustained elevation of FoxP3, posttransplant CD8 T cells also maintained markedly higher expression levels of latency-associated peptide (LAP), CD103, PD-1, PD-L1, and CTLA-4, as compared with pretransplant CD8 T cells that were identically treated by a one-time activation and rest in short-term culture. The posttransplant CD8 regulatory T cells (Treg) have autoantigen-specific and nonspecific suppressive activity, which is contact independent and predominantly TGF-β dependent. By contrast, the pretransplant CD8 T cells have helper activity, which is cell contact dependent. Although CD4⁺CD25^high Treg cells return during clinical remission of conventional drug-treated lupus, the posttransplant patient’s CD8 Treg cells are considerably more potent, and they are absent in drug-treated patients in whom CD4 T cell autoreactivity to nucleosomal epitopes persists even during clinical remission. Therefore, unlike conventional drug therapy, hemopoietic stem cell transplantation generates a newly differentiated population of LAP^highCD103^high CD8^TGF-β Treg cells, which repairs the Treg deficiency in human lupus to maintain patients in true immunological remission.

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 with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant RO1 AR39157 (to S.K.D.), Lupus Foundation of America (to R.K.B.), and National Institutes of Health Grant P60 AR30692 (to R.R.G.).

² Address correspondence and reprint requests to Dr. Syamal K. Datta, Division of Rheumatology, Northwestern University Feinberg School of Medicine, 240 East Huron Street, McGaw No. M300, Chicago, IL 60611. E-mail address: skd257{at}northwestern.edu

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; Treg, regulatory T cells; HSCT, hemopoietic stem cell transplantation; SLEDAI, SLE disease activity index; CRI, cytokine response index; LAP, latency-associated peptide; CFC, cytokine flow cytometry; aSLE, active SLE; iSLE, inactive SLE; CD62L, L-selectin.