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

Shahram Kordasti, Benedetta Costantini, Thomas Seidl, Pilar Perez Abellan, Marc Martinez Llordella, Donal McLornan, Kirsten E. Diggins, Austin Kulasekararaj, Cinzia Benfatto, Xingmin Feng, Alexander Smith, Syed A. Mian, Rossella Melchiotti, Emanuele de Rinaldis, Richard Ellis, Nedyalko Petrov, Giovanni A. M. Povoleri, Sun Sook Chung, N. Shaun B. Thomas, Farzin Farzaneh, Jonathan M. Irish, Susanne Heck, Neal S. Young, Judith C. W. Marsh and Ghulam J. Mufti

Key Points

  • Mass cytometry reveals a Treg immune signature for AA and for response to antithymocyte globulin.

  • AA Tregs in vitro are expandable, stable, and functional, with potential for future therapeutic options.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Abstract

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 FOXP3hi, CD127lo 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.

  • Submitted March 23, 2016.
  • Accepted June 1, 2016.
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