MHC-derived allopeptide activates TCR-biased CD8+ Tregs and suppresses organ rejection
Elodie Picarda, … , Ignacio Anegon, Carole Guillonneau
Elodie Picarda, … , Ignacio Anegon, Carole Guillonneau
Published May 1, 2014
Citation Information: J Clin Invest. 2014;124(6):2497-2512. https://doi.org/10.1172/JCI71533.
View: Text | PDF
Research Article Immunology

MHC-derived allopeptide activates TCR-biased CD8+ Tregs and suppresses organ rejection

Abstract

In a rat heart allograft model, preventing T cell costimulation with CD40Ig leads to indefinite allograft survival, which is mediated by the induction of CD8+CD45RClo regulatory T cells (CD8+CD40Ig Tregs) interacting with plasmacytoid dendritic cells (pDCs). The role of TCR-MHC-peptide interaction in regulating Treg activity remains a topic of debate. Here, we identified a donor MHC class II–derived peptide (Du51) that is recognized by TCR-biased CD8+CD40Ig Tregs and activating CD8+CD40Ig Tregs in both its phenotype and suppression of antidonor alloreactive T cell responses. We generated a labeled tetramer (MHC-I RT1.Aa/Du51) to localize and quantify Du51-specific T cells within rat cardiac allografts and spleen. RT1.Aa/Du51-specific CD8+CD40Ig Tregs were the most suppressive subset of the total Treg population, were essential for in vivo tolerance induction, and expressed a biased, restricted Vβ11-TCR repertoire in the spleen and the graft. Finally, we demonstrated that treatment of transplant recipients with the Du51 peptide resulted in indefinite prolongation of allograft survival. These results show that CD8+CD40Ig Tregs recognize a dominant donor antigen, resulting in TCR repertoire alterations in the graft and periphery. Furthermore, this allopeptide has strong therapeutic activity and highlights the importance of TCR-peptide-MHC interaction for Treg generation and function.

Authors

Elodie Picarda, Séverine Bézie, Vanessa Venturi, Klara Echasserieau, Emmanuel Mérieau, Aurélie Delhumeau, Karine Renaudin, Sophie Brouard, Karine Bernardeau, Ignacio Anegon, Carole Guillonneau

×

Figure 5

In vitro and in vivo suppressive potential of Du51-specific CD40IgCD8+ Tregs.

Options: View larger image (or click on image) Download as PowerPoint
In vitro and in vivo suppressive potential of Du51-specific CD40IgCD8+ T...
(A) The relative proportion of CFSE-labeled LEW.1A dividing CD4+CD25– T cells stimulated with either donor LEW.1W (direct pathway) or alloantigen-loaded recipient LEW.1A (indirect pathway) pDCs was analyzed after 6 days of culture in the absence or presence of LEW.1A naive, total, Tet–, or Tet+ CD8+CD40Ig Tregs at a 1:1 effector/suppressor ratio. The proportion of dividing CD4+CD25– T cells in the control proliferation condition with pDCs only represented approximately 80% of the cells on day 6 and was given a value of 100 in each experiment. Graphs represent the mean ± SEM of the relative proportion of dividing CD4+CD25– T cells. *P < 0.05. n = 4. (B) 2.5 × 106 total or Tet– CD8+CD40Ig Tregs were injected i.v. into sublethally irradiated recipients (LEW.1A) the day before heart allotransplantation (LEW.1W). Graft survival was assessed by abdominal palpation of cardiac beating. **P < 0.01 for total (n = 4) versus Tet– CD8+CD40Ig Tregs (n = 3).