Subpopulations of T Regulatory Cells in Blood Stem Cell Harvests Influence Development of Acute Graft Versus Host Disease in Allogeneic Transplant Recipients.

Abstract

CD4+ FoxP3+ regulatory T cells (Tregs) are the potent suppressors of activation and proliferation of conventional T cells. Tregs subdivided by their expression of FoxP3 and CD45RA identify clinically important functional subsets. We analyzed Treg subpopulations in hematopoietic stem cell harvests (SCH) from 22 allogeneic (matched unrelated and sibling) donors with flow cytometry by their expression of CD45RA, CD127, CD25, and FoxP3 marker combinations. A high fraction of "activated Tregs", defined as CD4+ FoxP3hi CD45RAlo (aTreg) cells relative to all CD4+ T-cells, in the SCH correlated with no subsequent development of acute graft-versus-host disease (aGVHD) in the corresponding transplant recipients (aTreg 1.29%, range 0.96-1.64%, vs. 0.23%, range 0.14-0.56%, with subsequent aGvHD; P=0.0015). The "non-Treg" cells, defined by CD4+ FoxP3med/lo CD45RAlo , and resting Treg (rTreg) cells, defined by CD4+ FoxP3med CD45RAhi , did not correlate with aGvHD development. We also showed that phenotypic aTregs could be induced in vitro from nonTregs under homeostatic proliferation conditions and that this ability correlated with the CD127 and CD25 expression patterns. We identified a subset of T CD4+ FoxP3+ cells, i.e., aTregs that were correlated to aGvHD development, and demonstrated plasticity of the nonTreg population to provide phenotypic aTregs. This could have both a predictive clinical relevance in inflammatory conditions as well as support a rationale for development of cell targeted therapy. © 2016 International Clinical Cytometry Society.