2010 - TTS International Congress


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Immune Regulation and Tolerance I

97.7 - The direct alloreactivity pathway is more susceptible to regulation by nTreg than the indirect pathway.

Presenter: Grégory, Noël, Laval, Canada
Authors: Noël G., Daniel C.

THE DIRECT ALLOREACTIVITY PATHWAY IS MORE SUSCEPTIBLE TO REGULATION BY NTREG THAN THE INDIRECT PATHWAY.

IMMUNE REGULATION AND TOLERANCE I

G. Noël1, C. Daniel2
1Iaf (institut Armand-frappier), INRS (Institut National de la Recherche Scientifique, Laval/CANADA, 2Iaf, INRS, Laval/CANADA

Body: Our laboratory has developed a TCR transgenic model which allows us to independently study direct and indirect pathways during CD4+ T cell-mediated rejection of skin graft. This model is based on thedual specificity of the 2.102 clonotype for two different ligands in vivo: the MHC II I-Ep on the surface of B10.P mice APCs (direct pathway) and the Hb(64-76)peptide (expressed by B6(mHEL-Hb) mice)after uptake, processing and presentation by MHC II I-Ek on self APCs (indirect pathway). Using alpha/beta T cell-deficient mice reconstituted with purified CD4+ T cells from 2.102 TCR Tg mice(2.102Tg), we showed that kinetics of graft rejection are identical for both pathways, though graft infiltration by effector T cells occurs more rapidly in the direct pathway. We hypothesized thatregulatory T cells could be responsible for this delay in rejection. We first characterized the T cells from 2.102Tg mice and showed the presence of a CD4+ subpopulation (10% of the CD4+) whichexpress the classic phenotype of the CD4+ natural regulatory T cells (nTreg): CD25+, Foxp3+, CD45Rb low. These cells were able to specifically suppress the proliferation of 2.102Tg CD4+ T cells invitro and to proliferate when stimulated by the Hb(64-76) peptide in the presence of IL-2, in contrast to WT (non-transgenic) nTreg. Thus, we demonstrated the presence of antigen-specific 2.102TgnTreg in the CD4+ T cell population from these mice. Moreover, these nTreg were able to specifically delay allogeneic skin graft rejection mediated by the CD4+CD25- T cells from WT mice only when theHb(64-76) peptide was present in the allograft, confirming their suppression activity in vivo. The ratio CD4+CD25-:nTreg used in these experiments was 2:1. We then explored the 2.102Tg nTregregulatory activity in our model in more physiological conditions, where the effector:nTregs ratio is reflective of that observed in normal individuals (approximately 10:1). Depletion of the CD25+cells in the population of purified CD4+ 2.102Tg T cells adoptively transferred to alpha/beta T cell-deficient mice significantly accelerated allograft rejection by the direct pathway only. Thisobservation correlated with increased graft infiltration by 2.102Tg T cells and IFN gamma production between day 7 and day 10 post-transplant, in contrast to conditions where nTregs were co-injected.Our results suggest that regulatory T cells are able to control the early stage of rejection in the allograft, and the direct pathway seems to be more sensitive to this regulation than the indirect.We are currently assessing the role of nTregs in the activation, proliferation and differentiation of 2.102Tg effector T cells in secondary lymphoid organs in order to highlight how these twopathways might be differently sensitive to nTreg regulation.

Disclosure: All authors have declared no conflicts of interest.


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