Submitted January 9, 2007
Accepted February 10, 2007
Effector and regulatory T cell function is differentially regulated by RelB within
antigen presenting cells during GVHD
Kelli PA MacDonald, Rachel D Kuns, Vanessa Rowe, Edward S Morris, Tatjana Banovic, Helen Bofinger, Brendan O'Sullivan, Kate A Markey, Alistair L Don, Ranjeny Thomas, and Geoffrey R Hill*
Bone Marrow Transplantation Laboratory, The Queensland Institute of Medical Research, Herston, Australia
Centre for Immunology and Cancer Research, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Australia
* Corresponding author; email: geoff.hill{at}qimr.edu.au.
Antigen presenting cells (APC) are critical for the initiation of graft-versus host disease (GVHD) although the responsible APC subset and molecular mechanisms remain unclear. Since dendritic cells (DC) are the most potent APC and the NF-kB/Rel family member RelB is associated with DC maturation and potent APC function, we examined their role in GVHD. Within four hours of total body irradiation, RelB nuclear translocation was increased and restricted to CD11chi DC within the host APC compartment. Furthermore, the transient depletion of CD11chi donor DC that reconstitute in the second week after transplant resulted in a transient decrease in GVHD severity. By using RelB-/- bone marrow chimeras as transplant recipients or RelB-/- donor bone marrow we demonstrate that the induction and maintenance of GVHD is critically dependent on this transcription factor within both host and donor APC. Critically, RelB within APCs was required for the expansion of donor Th1 effectors and subsequent alloreactivity, but not the peripheral expansion or function of donor FoxP3+ regulatory T cells. These data suggest that the targeted inhibition of nuclear RelB translocation within APC represents an attractive therapeutic strategy to dissociate effector and regulatory T cell function in settings of Th1 mediated tissue injury.
