A new T-cell receptor transgenic model of the CD4+ direct pathway: level of priming determines acute versus chronic rejection.
BACKGROUND
T-cell receptor transgenic (TCR-tg) mouse models with direct CD4 alloreactivity will help elucidate mechanisms of transplant rejection and tolerance in vivo. Although such models exist, they are limited by unusual strain combinations or are based on model antigens.


METHODS
A TCR-tg mouse with direct CD4 specificity in the widely used BALB/c donor --> C57BL/6 host strain combination was created. This TCR-tg mouse, named 4C, was selected for reactivity against BALB/c dendritic cells in order to model early priming events after transplantation. The response of 4C T cells to skin and heart transplants were characterized.


RESULTS
The alloantigen is restricted by I-A and appears to be widely distributed in mouse tissues. 4C T cells are able to acutely reject skin but not heart allografts. Paradoxically, heart grafts elicited a stronger proliferation and effector function of TCR-tg T cells than skin grafts. 4C T cells caused cardiac allograft vasculopathy in the absence of other T cells and alloantibodies, suggesting a role for the direct pathway in chronic rejection. Augmentation of priming with an infusion of donor-derived dendritic cells resulted in acute heart allograft rejection by 4C T cells, demonstrating that the level of priming can play a role in determining acute versus chronic rejection by the CD4 direct pathway.


CONCLUSIONS
Rejection of a graft by the direct CD4 pathway is determined by graft susceptibility to rejection, as well as the degree of T-cell priming caused by the graft. Grafts that are not acutely rejected can develop transplant vasculopathy mediated by the direct CD4 T cells.
Brennan
Todd V
TV
Transplantation Research Laboratory, Division of Transplantation, Department of Surgery, University of California San Francisco, San Francisco, CA 94143-0780, USA.
Hoang
Vunghi
V
Garrod
Kym R
KR
Liu
Feng-Chun
FC
Hayden
Tracy
T
Kim
Jim
J
Kang
Sang-Mo
SM
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology*; D017931:DNA Primers; D003713:Dendritic Cells / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*
D015704:CD4 Antigens; D017931:DNA Primers; D000949:Histocompatibility Antigens Class II; D011948:Receptors, Antigen, T-Cell