Clonal Deletion Established via Invariant NKT Cell Activation and Costimulatory Blockade Requires in Vivo Expansion of Regulatory T Cells

Toshihito Hirai, R. Ishii, S. Miyairi, M. Ikemiyagi, K. Omoto, Y. Ishii, K. Tanabe

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Recently, the immune-regulating potential of invariant natural killer T (iNKT) cells has attracted considerable attention. We previously reported that a combination treatment with a liposomal ligand for iNKT cells and an anti-CD154 antibody in a sublethally irradiated murine bone marrow transplant (BMT) model resulted in the establishment of mixed hematopoietic chimerism through in vivo expansion of regulatory T cells (Tregs). Herein, we show the lack of alloreactivity of CD8+T cells in chimeras and an early expansion of donor-derived dendritic cells (DCs) in the recipient thymi accompanied by a sequential reduction in the donor-reactive Vβ-T cell receptor repertoire, suggesting a contribution of clonal deletion in this model. Since thymic expansion of donor DCs and the reduction in the donor-reactive T cell repertoire were precluded with Treg depletion, we presumed that Tregs should preform before the establishment of clonal deletion. In contrast, the mice thymectomized before BMT failed to increase the number of Tregs and to establish CD8+T cell tolerance, suggesting the presence of mutual dependence between the thymic donor-DCs and Tregs. These results provide new insights into the regulatory mechanisms that actively promote clonal deletion.

Original languageEnglish (US)
Pages (from-to)426-439
Number of pages14
JournalAmerican Journal of Transplantation
Volume16
Issue number2
DOIs
StatePublished - Feb 1 2016
Externally publishedYes

Bibliographical note

Publisher Copyright:
Copyright © 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Keywords

  • basic (laboratory) research/science
  • immunobiology
  • immunosuppression/immune modulation
  • tolerance: chimerism
  • tolerance: costimulation blockade
  • tolerance: experimental
  • tolerance: mechanisms

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