The role of plasmacytoid dendritic cells in the induction of dominant immune tolerance
Final Report Abstract
CCR9 is a homing receptor that targets lymphocytes to the thymus and the intestines in response to the ligand CCL25. Seminal studies in the Butcher lab revealed that pDCs express CCR9 in the immature state, while they downregulate the receptor upon immune stimulation through toll like receptors. Further, CCR9+ pDCs were protective in a mouse model of graft versus host disease. Following key questions arising from these findings guided my research: Can CCR9 target tolerogenic pDCs to thymus? What is the role of CCR9+ pDCs, and of pDC-expressed CCR9, in central (thymic) tolerance? Injecting labeled dextran (or labeled beads) subcutaneously into mice allowed us to monitor antigenic uptake by pDCs. We were able to detect pDCs in the thymus that had taken up the fluorescent material. Several control experiments ensured that we indeed tracked pDC-mediated antigen-delivery to the thymus. The delivery was blocked upon immune stimulation by the TLR9 ligand CpG. Using an ovalbumin T cell receptor transgenic approach, we measured clonal deletion upon pDC delivery of OVA to the thymus. This study showed that pDCs indeed transported antigens to the thymus to induce tolerance. This pathway was abrogated in the presence of a “danger signal”, preventing tolerance to harmful agents. Immune tolerance in the intestines is in part dependent on systemic mechanisms involving the thymus. However, the intestinal immune system also comprises additional mechanisms that allow for tissue specific immune responses necessary for homeostasis at this highly challenged site. On such mechanism is secretory IgA induction. Having established a role for pDCs in central tolerance, I asked the question if pDCs, highly abundant in the gut, may also assure homeostasis through interacting with B cell in IgA induction. Using rotavirus as a model organism, I monitored the dependency of B cells on pDCs in the production of rotavirus-specific IgA. Indeed, pDCs proved important for optimal RV specific IgA induction through their high capacity of type I IFN production. Currently, I follow up on requirements of pDCs in IgA induction by asking whether pDCs exert their function through a crosstalk with cDCs. I characterized cDCs in more detail in order to define the most likely candidates. Interestingly, intestinal cDC subsets reciprocally depend on Bcl6 and Blimp-1, two transcription factors extremely important in B and T cell fate decisions.
Publications
- Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance. Immunity 2012; 36(3):438-50
Hadeiba, H., Lahl, K., Edalati, A., Oderup, C., Habtezion, A., Pachynski, R., Nguyen, L., Ghodsi, A., Adler, S., E. C. Butcher
- Comparative transcriptional and functional profiling defines conserved programs of intestinal DC differentiation in humans and mice. Nat. Immunology Dec 2013
Watchmaker, P.W., Lahl, K., Lee, M., Baumjohann, D., Morton, J., Kim, S.J., Zeng, R., Dent, A, Ansel, K.M., Diamond, B., Hadeiba, H. and E.C. Butcher
(See online at https://doi.org/10.1038/ni.2768) - Plasmacytoid dendritic cells promote rotavirus-induced human and murine B cell responses. JCI 2013; 123(6):2464-74
Deal, E.M., Lahl, K., Narvaez, C.F., Butcher, E.C., H.B. Greenberg
