Deep-phenotyping of Tregs identifies an immune signature for idiopathic aplastic anemia and predicts response to treatment

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 - https://www.scopus.com/pages/publications/85011904114

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 -