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 lupus

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Abstract

Compared with conventional drug therapy, autologous hemopoietic stem cell transplantation (HSCT) can induce very-longterm remission in refractory lupus patients. Herein, we show that in posttransplant patients, both CD4 +CD25highFoxP3+ 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+CD25high 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 LAPhighCD103high CD8TGF-β Treg cells, which repairs the Treg deficiency in human lupus to maintain patients in true immunological remission.

Original languageEnglish (US)
Pages (from-to)6346-6358
Number of pages13
JournalJournal of Immunology
Volume183
Issue number10
DOIs
StatePublished - Nov 15 2009

ASJC Scopus subject areas

  • Immunology

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