Clonal Deletion Established via Invariant NKT Cell Activation and Costimulatory Blockade Requires In Vivo Expansion of Regulatory T Cells.
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.
Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.
T
T
Hirai
Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.
R
R
Ishii
Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.
S
S
Miyairi
Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.
M
M
Ikemiyagi
Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.
K
K
Omoto
Laboratory for Vaccine Design, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Y
Y
Ishii
Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.
K
K
Tanabe
D000818:Animals; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D046528:Chimerism; D017637:Clonal Deletion / Q000276:immunology*; D005434:Flow Cytometry; D006085:Graft Survival; D007108:Immune Tolerance / Q000276:immunology*; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000276:immunology*; D016038:Skin Transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*; D014019:Tissue Donors
basic (laboratory) research/science; immunobiology; immunosuppression/immune modulation; tolerance: chimerism; tolerance: costimulation blockade; tolerance: experimental; tolerance: mechanisms