INDIRECT T-CELL ALLORECOGNITION AND ALLOANTIBODY-MEDIATED REJECTION OF MHC CLASS-I DISPARATE HEART GRAFTS

Recent studies in the rat have identified a role for T cell-dependent alloantibody in rejection of MHC class I-disparate allografts, RT1A(a) -disparate PVG.R8 heart grafts are rejected acutely in naive, and hype racutely in sensitized, PVG.RT1(o) recipients by CD4 T cell dependent alloantibody, Here, we examined the T cell Ag recognition pathways res ponsible and show that direct injection into skeletal muscle of plasmi d DNA, encoding a water-soluble form of the RT1A(a) RMC class I heavy chain (pcmu-tA(a)), stimulates IgG2b cytotoxic alloantibody and marked ly accelerates rejection of PVG.R8 heart grafts (median survival time 2 days), pcmu-tA(a) injection did not induce CTL to A(a), arguing agai nst direct allorecognition of soluble A(a). Treatment with mAbs confir med that the alloimmune response to pcmu-tA(a) injection depended on C D4, not CD8, T cells. Priming T cells for indirect allorecognition by injection of 15-mer peptides spanning the alpha 1 and alpha 2 domains of A(a) failed to stimulate anti-A(a) Ab but caused an accelerated Ab response to a PVG.R8 heart and a modest acceleration in graft rejectio n (median survival time 4 days), These results suggest that both solub le MHC class I and allopeptides prime CD4 T cells by the indirect path way, but that soluble class I is a more effective immunogen for humora l alloimmunity because its tertiary protein structure provides B cell epitopes, We propose that priming humoral alloimmunity, like CTL primi ng, requires recognition of intact MHC on donor cells? but essential T cell help can be provided by CD4 T cells recognizing allogeneic class I exclusively by the indirect pathway.