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Contribution of regulatory T cells and effector T cell deletion in tolerance induction by costimulation blockade
- Source :
- ResearcherID
- Publication Year :
- 2008
-
Abstract
- Blocking of costimulatory signals for T cell activation leads to tolerance in several transplantation models, but the underlying mechanisms are incompletely understood. We analyzed the involvement of regulatory T cells (Treg) and deletion of alloreactive cells in the induction and maintenance of tolerance after costimulation blockade in a mouse model of graft-vs-host reaction. Injection of splenocytes from the C57BL/6 parent strain into a sublethally irradiated F(1) offspring (C57BL/6 x C3H) induced a GVHR characterized by severe pancytopenia. Treatment with anti-CD40L mAb and CTLA4-Ig every 3 days during 3 wk after splenocyte injection prevented disease development and induced a long-lasting state of stable mixed chimerism (>120 days). In parallel, host-specific tolerance was achieved as demonstrated by lack of host-directed alloreactivity of donor-type T cells in vitro and in vivo. Chimerism and tolerance were also obtained after CD25(+) cell-depleted splenocyte transfer, showing that CD25(+) natural Treg are not essential for tolerance induction. We further show that costimulation blockade results in enhanced Treg cell activity at early time points (days 6-30) after splenocyte transfer. This was demonstrated by the presence of a high percentage of Foxp3(+) cells among donor CD4(+) cells in the spleen of treated animals, and our finding that isolated donor-type T cells at an early time point (day 30) after splenocyte transfer displayed suppressive capacity in vitro. At later time points (>30 days after splenocyte transfer), clonal deletion of host-reactive T cells was found to be a major mechanism responsible for tolerance. ispartof: Journal of Immunology vol:181 issue:2 pages:1034-1042 ispartof: location:United States status: published
- Subjects :
- Adoptive cell transfer
T cell
Immunology
CD40 Ligand
Graft vs Host Disease
Lymphocyte Activation
T-Lymphocytes, Regulatory
Clonal deletion
Mice
Antigens, CD40
CD28 Antigens
Antigens, CD80
Splenocyte
medicine
Immunology and Allergy
Animals
IL-2 receptor
CD40 Antigens
Mice, Inbred C3H
Transplantation Chimera
CD40
biology
Antigens, CD28
FOXP3
Forkhead Transcription Factors
Antigens, CD86
Adoptive Transfer
Mice, Inbred C57BL
Tolerance induction
medicine.anatomical_structure
biology.protein
B7-1 Antigen
Female
Transplantation Tolerance
B7-2 Antigen
T-Lymphocytes, Cytotoxic
Subjects
Details
- ISSN :
- 15506606
- Volume :
- 181
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Accession number :
- edsair.doi.dedup.....04cd56370c7bba84bc06ee6445447f94