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. RT1Aa-disparate PVG.R8 heart grafts are rejected acutely in naive, and hyperacutely in sensitized, PVG.RTIu recipients by CD4 T cell-dependent alloantibody. Here, we examined the T cell Ag recognition pathways responsible and show that direct injection into skeletal muscle of plasmid DNA, encoding a water-soluble form of the RT1Aa MHC class I heavy chain (pcmu-tAa), stimulates IgG2b cytotoxic alloantibody and markedly accelerates rejection of PVG.R8 heart grafts (median survival time 2 days). pcmu-tAa injection did not induce CTL to Aa, arguing against direct allorecognition of soluble Aa. Treatment with mAbs confirmed that the alloimmune response to pcmu-tAa injection depended on CD4, not CD8, T cells. Priming T cells for indirect allorecognition by injection of 15-mer peptides spanning the alpha1 and alpha2 domains of Aa failed to stimulate anti-Aa Ab but caused an accelerated Ab response to a PVG.R8 heart and a modest acceleration in graft rejection (median survival time 4 days). These results suggest that both soluble MHC class I and allopeptides prime CD4 T cells by the indirect pathway, but that soluble class I is a more effective immunogen for humoral alloimmunity because its tertiary protein structure provides B cell epitopes. We propose that priming humoral alloimmunity, like CTL priming, 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.
Department of Surgery, University of Glasgow, Scotland, United Kingdom.
G J
GJ
Pettigrew
E
E
Lovegrove
J A
JA
Bradley
J
J
Maclean
E M
EM
Bolton
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D003602:Cytotoxicity, Immunologic; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology; D007273:Injections, Intramuscular; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007518:Isoantibodies / Q000502:physiology*; D007519:Isoantigens / Q000276:immunology*; D008212:Lymphocyte Depletion; D010455:Peptides / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D051381:Rats; D011919:Rats, Inbred Strains; D016038:Skin Transplantation / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019444:Vaccines, DNA / Q000276:immunology
D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D007518:Isoantibodies; D007519:Isoantigens; D010455:Peptides; D019444:Vaccines, DNA