TY - JOUR
T1 - Deep-phenotyping of Tregs identifies an immune signature for idiopathic aplastic anemia and predicts response to treatment
AU - Kordasti, Shahram
AU - Costantini, Benedetta
AU - Seidl, Thomas
AU - Perez Abellan, Pilar
AU - Martinez Llordella, Marc
AU - Mclornan, Donal
AU - Diggins, Kirsten E.
AU - Kulasekararaj, Austin
AU - Benfatto, Cinzia
AU - Feng, Xingmin
AU - Smith, Alexander
AU - Mian, Syed A.
AU - Melchiotti, Rossella
AU - De Rinaldis, Emanuele de
AU - Ellis, Richard
AU - Petrov, Nedyalko
AU - Povoleri, Giovanni A.M.
AU - Chung, Sun Sook
AU - Thomas, N. Shaun B.
AU - Farzaneh, Farzin
AU - Irish, Jonathan M.
AU - Heck, Susanne
AU - Young, Neal S.
AU - Marsh, Judith C.W.
AU - Mufti, Ghulam J.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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 (CyTOF) and an unbiased multidimensional analytical approach, we identified two specific human Treg subpopulations (Treg A and Treg B) with distinct phenotypes, gene-expression, expandability and function. Treg subpopulation B, predominates in IST responder patients, has a memory/activated phenotype (with higher expression of CD95, CCR4 and CD45RO within FOXP3hi, CD127lo Tregs), expresses the IL- 2/STAT5 pathway and cell-cycle commitment genes. Furthermore, in-vitro expanded Tregs become functional and with the characteristics of Treg subpopulation 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.
AB - 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 (CyTOF) and an unbiased multidimensional analytical approach, we identified two specific human Treg subpopulations (Treg A and Treg B) with distinct phenotypes, gene-expression, expandability and function. Treg subpopulation B, predominates in IST responder patients, has a memory/activated phenotype (with higher expression of CD95, CCR4 and CD45RO within FOXP3hi, CD127lo Tregs), expresses the IL- 2/STAT5 pathway and cell-cycle commitment genes. Furthermore, in-vitro expanded Tregs become functional and with the characteristics of Treg subpopulation 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.
UR - http://www.scopus.com/inward/record.url?scp=85011904114&partnerID=8YFLogxK
U2 - 10.1182/blood-2016-03-703702
DO - 10.1182/blood-2016-03-703702
M3 - Article
SN - 0006-4971
VL - 128
SP - 1193
EP - 1205
JO - Blood
JF - Blood
IS - 9
ER -
