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The promise of CD4+FoxP3+ regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem
cell transplantation
Ferrata Storti Foundation
Haematologica 2019 Volume 104(7):1309-1321
Sabrina Copsel,1* Dietlinde Wolf,2* Krishna V. Komanduri1,2,3 and Robert B. Levy1,3,4
1Department of Microbiology and Immunology; 2Sylvester Comprehensive Cancer Center; 3Division of Transplantation and Cellular Therapy, Department of Medicine and 4Department of Ophthalmology, Miller School of Medicine, University of Miami,
FL, USA
*SC and DW contributed equally to this work.
ABSTRACT
CD4+FoxP3+ regulatory T cells (Tregs) are a non-redundant population critical for the maintenance of self-tolerance. Over the past decade, the use of these cells for therapeutic purposes in transplantation and autoimmune disease has emerged based on their capacity to inhibit immune activation. Basic science discoveries have led to identifying key receptors on Tregs that can regulate their proliferation and function. Notably, the understanding that IL-2 signaling is crucial for Treg homeosta- sis promoted the hypothesis that in vivo IL-2 treatment could provide a strat- egy to control the compartment. The use of low-dose IL-2 in vivo was shown to selectively expand Tregs versus other immune cells. Interestingly, a number of other Treg cell surface proteins, including CD28, CD45, IL-33R and TNFRSF members, have been identified which can also induce activa- tion and proliferation of this population. Pre-clinical studies have exploited these observations to prevent and treat mice developing autoimmune dis- eases and graft-versus-host disease post-allogeneic hematopoietic stem cell transplantation. These findings support the development of translational strategies to expand Tregs in patients. Excitingly, the use of low-dose IL-2 for patients suffering from graft-versus-host disease and autoimmune dis- ease has demonstrated increased Treg levels together with beneficial out- comes. To date, promising pre-clinical and clinical studies have directly tar- geted Tregs and clearly established the ability to increase their levels and augment their function in vivo. Here we review the evolving field of in vivo Treg manipulation and its application to allogeneic hematopoietic stem cell transplantation.
Introduction
The identification of CD4+FoxP3+ regulatory T cells (Tregs) as a non-redundant cell population essential for the maintenance of peripheral self-tolerance has stim- ulated strong interest in their potential therapeutic application to promote allograft acceptance and ameliorate autoimmune diseases.1-5 The finding that Tregs are often present at tumor sites has also raised the prospect of augmenting antitumor immu- nity by diminishing their numbers or function.1,6-11 Accordingly, the fields of trans- plantation, autoimmunity and oncology have converged on a common objective to selectively manipulate the Treg compartment to inhibit or promote conventional T- cell (Tconv) antigen-specific adaptive immune responses.
Clinical procedures developed to harvest Tregs for study and therapeutic applica- tion have been primarily based on cell surface expression of CD4, CD25 and CD127.12-14 Employing magnetic bead or flow cytometric isolation methodology, viable and enriched preparations of Tregs have been generated for subsequent ex vivo expansion and translational use in patients.15-18 Inherent in such in vitro manipu-
Correspondence:
ROBERT B. LEVY
rlevy@med.miami.edu
Received: February 4, 2019. Accepted: May 7, 2019. Pre-published: June 20, 2019.
doi:10.3324/haematol.2018.198838
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/7/1309
©2019 Ferrata Storti Foundation
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