Regulatory T cells exhibit decreased proliferation but enhanced suppression after pulsing with sirolimus

K. Singh, N. Kozyr, L. Stempora, A. D. Kirk, C. P. Larsen, B. R. Blazar, L. S. Kean

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Although regulatory T cells (Tregs) suppress allo-immunity, difficulties in their large-scale production and in maintaining their suppressive function after expansion have thus far limited their clinical applicability. Here we have used our nonhuman primate model to demonstrate that significant ex vivo Treg expansion with potent suppressive capacity can be achieved and that Treg suppressive capacity can be further enhanced by their exposure to a short pulse of sirolimus. Both unpulsed and sirolimus-pulsed Tregs (SPTs) are capable of inhibiting proliferation of multiple T cell subpopulations, including CD4 + and CD8 + T cells, as well as antigen-experienced CD28 +CD95 + memory and CD28 -CD95 + effector subpopulations. We further show that Tregs can be combined in vitro with CTLA4-Ig (belatacept) to lead to enhanced inhibition of allo-proliferation. SPTs undergo less proliferation in a mixed lymphocyte reaction (MLR) when compared with unpulsed Tregs, suggesting that Treg-mediated suppression may be inversely related to their proliferative capacity. SPTs also display increased expression of CD25 and CTLA4, implicating signaling through these molecules in their enhanced function. Our results suggest that the creation of SPTs may provide a novel avenue to enhance Treg-based suppression of allo-immunity, in a manner amenable to large-scale ex vivo expansion and combinatorial therapy with novel, costimulation blockade-based immunosuppression strategies. A nonhuman primate model of regulatory T cell ex vivo expansion is used to demonstrate that these cells can downregulate memory as well as naive T cell function, combine effectively with belatacept to suppress alloproliferation, and be significantly increased by their exposure to a short pulse of sirolimus.

Original languageEnglish (US)
Pages (from-to)1441-1457
Number of pages17
JournalAmerican Journal of Transplantation
Volume12
Issue number6
DOIs
StatePublished - Jun 2012

Bibliographical note

Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.

Keywords

  • immunosuppression
  • regulatory T cells
  • sirolimus

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