Infusion of host derived ex vivo expanded regulatory T cells (eTregs) is an attractive therapeutic strategy for promotion of transplant tolerance. We report herein that human eTregs cultivated for in vivo therapy abundantly express the death molecules T-cell Immunoglobulin and Mucin domain-3 protein (TIM-3) and program death 1(PD-1), are highly potent yet fragile. We studied the functional and phenotypic features of sorted peripheral CD4+CD25hiCD127lo Tregs expanded in the presence of anti-CD3 and anti-CD28 coated micro beads and IL-2 for 14 days. Notably, >95% of eTregs generated using protocols under investigation for Treg cellular therapy are TIM-3+ of which ∼60% co-expressed PD-1, both molecules known to contribute to effector T cell apoptosis, exhaustion or dysfunction. Contrastingly, only ∼10% of nTregs in peripheral blood express TIM-3. Compared to their nTregs, expanded TIM-3+ Tregs are more potent suppressors of in vitro Teff proliferation and robustly express CD25, CTLA-4, CD39, CD45RO, IL-10, but are programmed for apoptotic cell death. Exposure to the TIM-3 ligand galectin-9 in a dose and time dependent manner or absence of a continuous proliferative micro environment led to eTreg death; though these cells could be rescued by TCR stimulation and/or IL-2. Thus these studies indicate that the highly potent eTregs are terminally differentiated Tregs expressing death molecules TIM-3 and PD-1 and may be short lived in vivo. As use of eTregs is a promising therapeutic strategy our findings provide further insight into novel properties and fate of expanded human Tregs instructive for advancement of Treg cellular therapeutic approaches.
To cite this abstract in AMA style:Gupta S, Samuels P, Long S, Tatum M, Buckner J. Ex Vivo Expanded Human Regulatory T Cells Are Potent Suppressors but May Be Short-Lived [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/ex-vivo-expanded-human-regulatory-t-cells-are-potent-suppressors-but-may-be-short-lived/. Accessed October 27, 2020.
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