Evidence for cooperativity in the rejection of cardiac grafts mediated by CD4 TCR Tg T cells specific for a defined allopeptide.
Understanding the mechanisms of rejection of organs transplanted between unrelated individuals is confounded by the complexity of the alloantigens and the diversity of T cells responding to these alloantigens. To circumvent these problems, we developed a transgenic (Tg) C57BL/6 model system in which the T-cell receptor (TCR) expressed by CD4 T cells is specific for a defined allogeneic H-2Kd peptide and the cardiac donor expressed H-2Kd as a transgene on the C57BL/6 background (B6.Kd). These TCR Tg T cells were previously shown to mediate rapid rejection of a B10.D2 cardiac allograft when transferred to Rag1 recipients, demonstrating that the "indirect" pathway of allorecognition is sufficient for complete rejection in the absence of other T cells or antibody. Here, we report that B6.Kd hearts were rejected in an accelerated fashion by Rag1(-/-) TCR Tg T cells adoptively transferred to normal B6 recipients. Rejection in this model was associated with large myocardial infarcts and significant coronary artery inflammation. Moreover, transferred TCR Tg CD4+ cells mediated allograft injury without the requirement for cytotoxic function from recipient-derived CD8 T cells. A non-linear relationship was observed between the initial precursor frequency of the antigen-specific TCR Tg cells and the ultimate tempo of acute rejection, which is taken as evidence for cooperativity between components of the system.
Honjo
Kazuhito
K
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35233-7331, USA.
Yan Xu
Xiao
X
Kapp
Judith A
JA
Bucy
R Pat
RP
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010455:Peptides / Q000276:immunology; D011401:Promoter Regions, Genetic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology*
D018398:Homeodomain Proteins; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; C064658:RAG-1 protein