Deep phenotyping of Tregs identifies an immune signature for idiopathic aplastic anemia and predicts response to treatment.
Idiopathic aplastic anemia (AA) is an immune-mediated and serious form of bone marrow failure. Akin to other autoimmune diseases, we have previously shown that in AA regulatory T cells (Tregs) are reduced in number and function. The aim of this study was to further characterize Treg subpopulations in AA and investigate the potential correlation between specific Treg subsets and response to immunosuppressive therapy (IST) as well as their in vitro expandability for potential clinical use. Using mass cytometry and an unbiased multidimensional analytical approach, we identified 2 specific human Treg subpopulations (Treg A and Treg B) with distinct phenotypes, gene expression, expandability, and function. Treg B predominates in IST responder patients, has a memory/activated phenotype (with higher expression of CD95, CCR4, and CD45RO within FOXP3(hi), CD127(lo) Tregs), expresses the interleukin-2 (IL-2)/STAT5 pathway and cell-cycle commitment genes. Furthermore, in vitro-expanded Tregs become functional and take on the characteristics of Treg B. Collectively, this study identifies human Treg subpopulations that can be used as predictive biomarkers for response to IST in AA and potentially other autoimmune diseases. We also show that Tregs from AA patients are IL-2-sensitive and expandable in vitro, suggesting novel therapeutic approaches such as low-dose IL-2 therapy and/or expanded autologous Tregs and meriting further exploration.
Department of Haematological Medicine, King's College London, London, United Kingdom; Haematological Medicine, King's College Hospital, London, United Kingdom;
Shahram
0000-0002-0347-4207
S
Kordasti
Department of Haematological Medicine, King's College London, London, United Kingdom; Haematological Medicine, King's College Hospital, London, United Kingdom;
Benedetta
B
Costantini
Department of Haematological Medicine, King's College London, London, United Kingdom;
Thomas
T
Seidl
Haematological Medicine, King's College Hospital, London, United Kingdom;
Pilar
P
Perez Abellan
Division of Transplantation Immunology & Mucosal Biology, King's College London, London, United Kingdom;
Marc
M
Martinez Llordella
Haematological Medicine, King's College Hospital, London, United Kingdom;
Donal
D
McLornan
Department of Cancer Biology, Vanderbilt University, Nashville, TN;
Kirsten E
KE
Diggins
Haematological Medicine, King's College Hospital, London, United Kingdom;
Austin
A
Kulasekararaj
Department of Haematological Medicine, King's College London, London, United Kingdom;
Cinzia
C
Benfatto
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; and.
Xingmin
X
Feng
Department of Haematological Medicine, King's College London, London, United Kingdom; Haematological Medicine, King's College Hospital, London, United Kingdom;
Alexander
A
Smith
Department of Haematological Medicine, King's College London, London, United Kingdom;
Syed A
SA
Mian
National Institute for Health Research Biomedical Research Centre, King's College London, London, United Kingdom.
Rossella
R
Melchiotti
National Institute for Health Research Biomedical Research Centre, King's College London, London, United Kingdom.
Emanuele
E
de Rinaldis
National Institute for Health Research Biomedical Research Centre, King's College London, London, United Kingdom.
Richard
R
Ellis
National Institute for Health Research Biomedical Research Centre, King's College London, London, United Kingdom.
Nedyalko
N
Petrov
Division of Transplantation Immunology & Mucosal Biology, King's College London, London, United Kingdom;
Giovanni A M
GA
Povoleri
Department of Haematological Medicine, King's College London, London, United Kingdom;
Sun Sook
SS
Chung
Department of Haematological Medicine, King's College London, London, United Kingdom;
N Shaun B
NS
Thomas
Department of Haematological Medicine, King's College London, London, United Kingdom;
Farzin
F
Farzaneh
Department of Cancer Biology, Vanderbilt University, Nashville, TN;
Jonathan M
JM
Irish
National Institute for Health Research Biomedical Research Centre, King's College London, London, United Kingdom.
Susanne
S
Heck
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; and.
Neal S
NS
Young
Department of Haematological Medicine, King's College London, London, United Kingdom; Haematological Medicine, King's College Hospital, London, United Kingdom;
Judith C W
JC
Marsh
Department of Haematological Medicine, King's College London, London, United Kingdom; Haematological Medicine, King's College Hospital, London, United Kingdom;
Ghulam J
GJ
Mufti
D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic / Q000276:immunology* / Q000628:therapy*; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D007165:Immunosuppression Therapy / Q000379:methods*; D007376:Interleukin-2 / Q000276:immunology; D053699:Interleukin-7 Receptor alpha Subunit / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology; D008297:Male; D008875:Middle Aged; D054398:Receptors, CCR4 / Q000276:immunology; D050799:STAT5 Transcription Factor / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology
C515354:CCR4 protein, human; C491901:FAS protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508594:IL2 protein, human; D007376:Interleukin-2; D053699:Interleukin-7 Receptor alpha Subunit; D054398:Receptors, CCR4; D050799:STAT5 Transcription Factor; D019014:fas Receptor; D017493:Leukocyte Common Antigens