ACTIVATION AND ROLE OF T REGULATORY CELLS

I.G. Harper¹, K. Saeb-parsy¹, C.J. Callaghan², R. Motallebzadeh¹, E.M. Bolton¹, J.A. Bradley³, G.J. Pettigrew^2
1Department Of Surgery, University of Cambridge, Cambridge/UNITED KINGDOM, ²Department Of Surgery, Addenbrooke's Hospital, University of Cambridge, Cambridge/UNITED KINGDOM, ³Transplant Surgery, Addenbrooke's Hospital NHS Trust, Cambridge/UNITED KINGDOM

Body: Introduction We have recently reported a role for autoantibody in the development of mouse heart graft vasculopathy that was surprisingly dependent upon donor CD4 T cells within the heart graft for its development. Regulatory T cells (Tregs) are important in protection against autoimmunity but in the presence of IL-6, their differentiation is instead skewed to a Th17 response, which may exacerbate disease. Here we examine the inverse reciprocal arrangement between the development of Th17 and Tregs in the development of autoantibody and allograft vasculopathy (AV). Methods The contribution of Tregs and Th17 T cells to AV and autoantibody development was studied in an MHC II-mismatched mouse model of heart transplantation, by treating recipients with either anti-CD25 (PC61 i.p. on day -1, 1, 3, 5, 7) or anti-IL-17 antibody (50μg i.v. on day 1,3,5 and weekly thereafter) and by adoptive transfer the day after transplant of naturally occurring CD25^+ve Tregs (nTregs) (purified from either donor or recipient strains). Graft survival was assessed by daily palpation and autoantibody production assayed by indirect immunofluorescence of nuclear-antigen-expressing HEp-2 cells. Results Anti IL-17 treatment of B6 recipients of bm12 hearts influenced neither development of autoantibody nor progression of AV. In contrast, depleting recipient Tregs markedly exacerbated autoantibody production and accelerated graft rejection (MST 20d vs. WT 95d). Heart grafts from CD4-T cell-depleted donors provoked significantly less autoantibody and survived longer (MST , p<0.01) than unmanipulated hearts in the Treg-depleted recipients, indicating that accelerated rejection following Treg depletion is partly due to exacerbation of humoral autoimmunity. Surprisingly, whereas adoptive transfer of recipient (B6) nTregs influenced neither autoantibody production nor allograft survival, transfer of donor (bm12) nTregs abrogated autoantibody and grafts survived indefinitely. Severity of AV in those recipients that received B6 nTregs was comparable to WT controls (mean intimal stenosis 70.29% ), whereas all allograft vessels in recipients that received bm12 nTregs were disease free. Conclusion Our results demonstrate a previously unrealized mechanism whereby Tregs contribute to graft survival by preventing effector autoantibody responses. We hypothesise that donor nTregs are more effective than recipient Tregs at preventing graft-versus-host mediated autoimmunity because they recognise the same target ligand (MHC class II on host autoreactive B cells) as is recognised by the population of donor, helper CD25^-ve CD4 T cells that are passengers within the heart .

Disclosure: All authors have declared no conflicts of interest.