Optimizing human Treg immunotherapy by Treg subset selection and E-selectin ligand expression

Abstract

While human Tregs hold immense promise for immunotherapy, their biologic variability poses challenges for clinical use. Here, we examined clinically-relevant activities of defined subsets of freshly-isolated and culture-expanded human PBMC-derived Tregs. Unlike highly suppressive but plastic memory Tregs (memTreg), naïve Tregs (nvTreg) exhibited the greatest proliferation, suppressive capacity after stimulation, and Treg lineage fidelity. Yet, unlike memTregs, nvTregs lack Fucosyltransferase VII and display low sLeX expression, with concomitant poor homing capacity. In vitro nvTreg expansion augmented their suppressive function, but did not alter the nvTreg sLeX-l ° w glycome. However, exofucosylation of the nvTreg surface yielded high sLeX expression, promoting endothelial adhesion and enhanced inhibition of xenogeneic aGVHD. These data indicate that the immature Treg glycome is under unique regulation and that adult PBMCs can be an ideal source of autologous-derived therapeutic Tregs, provided that subset selection and glycan engineering are engaged to optimize both their immunomodulation and tropism for inflammatory sites.

Associations of Th2, Th17, Treg cells, and IgA+ memory B cells with atopic disease in children: The Generation R Study

“…Interestingly, when studying Tregs divided in naive and memory Tregs, the association was mainly explained by memory Treg cells. The naive and memory Tregs have been shown to be two distinct subsets . Naive Treg cells derive from the thymus, whereas the production of memory Treg cells is induced peripherally .…”

“…While naive Tregs mostly originate from the thymus, memory Tregs are induced in the periphery and display the highest suppressive ability. 11,12 Insights into the biology of the cells that produce IgE are limited. In contrast to B cells expressing other Ig isotypes (IgM, IgD, IgA or IgG), IgE-expressing B cells are scarce and surface expression of IgE on these cells is low.…”

Ex vivo generation of umbilical cord blood T regulatory cells expressing the homing markers CD62L and cutaneous lymphocyte antigen

“…A recent clinical trial was initiated to test whether enforced fucosylation on CB Tregs infused prophylactically would improve homing and prevent GVHD in HSCT transplantation settings (Kellner et al unpublished findings). Recent evidence has confirmed that Tregs express fucosyltransferases, important enzymes in establishing fucose on siayl-Lewis x thus creating the CLA determinant on PSGL-1 [ 18 ]. The significant increase in CLA induced by the ex vivo culturing of CB Tregs in SCGM medium could supplant the need for exofucosylation of Tregs upon harvesting the expansion culture.…”

Role of Regulatory T Cells in Disturbed Immune Homeostasis in Patients With Chronic Obstructive Pulmonary Disease

“…This is a milestone in optimizing the efficacy of human Treg immunotherapy by selecting functionally different subpopulations of Tregs and identifying the ideal source of Tregs. Thus far, > 40 Treg subpopulation divisions defined by different surface molecules have been reported (51,52).…”