Regulatory T cell (Treg) subsets return in patients with refractory lupus following stem cell transplantation, and TGF-beta-producing CD8+ Treg cells are associated with immunological remission of lupus.
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(high)FoxP3(+) 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-beta 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(high)CD103(high) CD8(TGF-beta) Treg cells, which repairs the Treg deficiency in human lupus to maintain patients in true immunological remission.
Zhang
Li
L
Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Bertucci
Anne M
AM
Ramsey-Goldman
Rosalind
R
Burt
Richard K
RK
Datta
Syamal K
SK
D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism; D060890:B7-H1 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D060908:CTLA-4 Antigen; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D039001:Integrin alpha Chains / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000378:metabolism / Q000601:surgery*; D008297:Male; D008875:Middle Aged; D009707:Nucleosomes / Q000276:immunology / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor; D012075:Remission, Spontaneous; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D039001:Integrin alpha Chains; D018793:Interleukin-13; D009707:Nucleosomes; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D016212:Transforming Growth Factor beta; C091367:alpha E integrins; D007371:Interferon-gamma