Abstract
CD4+ Regulatory T cells (Treg) play a critical role in maintaining immune homeostasis. Various Treg subsets have been identified, however the heterogeneity of Treg subpopulations during development remains uncharacterized. Using mass cytometry we obtained single cell data on expression of 35 functional markers to examine the heterogeneity of Treg cells at birth and in adults. Unsupervised clustering algorithms FlowSOM and ACCENSE were used to quantify Treg heterogeneity. As expected, Treg in umbilical cord blood were predominately naïve while Treg in adult blood were predominately central memory and effector memory cells. Although umbilical cord blood Treg are mostly naïve cells, we observed multiple phenotypic Treg subsets in cord blood. Nevertheless, peripheral blood in adults contained higher percentages of Treg and the heterogeneity of Treg was significantly increased in adults. We also studied Treg heterogeneity throughout a 2-year period after allogeneic hematopoietic stem cell transplantation (alloHSCT) and in patients with chronic graft-versus-host disease (cGVHD). Treg heterogeneity recovered rapidly after alloHSCT and gradually increased in the first two years post-transplant. However, patients with cGVHD had significantly fewer distinct Treg subpopulations, proposing a correlation between a disrupted Treg heterogeneity and cGVHD. Our study is the first to compare human Treg heterogeneity at birth, in healthy adults and in patients after alloHSCT with and without cGVHD. This approach to characterize Treg heterogeneity based on expression of a large panel of functional markers may enable future studies to identify specific Treg defects that contribute to immune dysfunction.
Highlights
Regulatory T cells (Tregs) are essential elements of a healthy immune system
Using mass cytometry and advanced computational algorithms to simultaneously measure expression of 35 phenotypic and functional markers in individual cells, we undertook a detailed analysis of Treg heterogeneity in humans
Our study initially focused on Treg in umbilical cord blood and peripheral blood in healthy adults and subsequently was expanded to include Tregs reconstituting after allogeneic HSCT and in patients with chronic graft-versus-host disease (cGVHD)
Summary
Regulatory T cells (Tregs) are essential elements of a healthy immune system. They comprise between 5–10% of the peripheral blood CD4+ T cell compartment in healthy individuals and play a critical role protecting their host against immunopathological damage following inflammatory or immunological challenges [1, 2]. Tregs originate in the thymus and can be identified by expression of CD3, CD4, high levels of surface CD25, low levels of CD127 and intracellular FoxP3 [6]. Naïve Tregs express high levels of CD45RA and low levels of CD45R0 and FoxP3, whereas memory Tregs are FoxP3hi and CD45RA- [8, 9]. Recent thymic emigrants (RTE), which co-express CD31 and CD45RA, are still present in adults constituting up to 11% of all naive Tregs
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