Transferrin receptor in T cell activation and transplantation

Abstract

Transferrin receptor (TfR) expression is up-regulated during T cell activation after the interaction of the T cell receptor with the antigen- major histocompatibility complex and the expression of interleukin-2 (IL-2) receptor. We hypothesize that anti-TfR monoclonal antibody (mAb) will prolong allograft survival by altering T cell responses. In a murine heterotopic nonvascularized cardiac allograft model, CBA/J (H-2(κ)) recipients were transplanted with neonatal C57BL/6 (H-2(b)) donor hearts. Anti-TfR or isotype-matched control mAbs (100 μg) were administered at the time of transplantation and on the following day. Splenocytes from naive CBA/J mice were stimulated in vitro with C57BL/6 alloantigen. Anti-TfR mAb was administered at 5 μg]mL during the initiation of culture. Cytotoxic T lymphocyte (CTL) and mixed lymphocyte responses (MLR) were performed to assess T cell function. After 24 h in culture, cells were harvested, RNA isolated, and semi-quantitative reverse transcriptase-polymerase chain reaction performed. Anti-TfR mAb prolonged allograft survival to 25.7 ± 0.9 days compared to the isotype control (10.7 ± 0.4 days, P < 0.01, Wilcoxon rank sum). Anti-TfR mAb completely abrogated the CTL response and suppressed the MLR by 70-86% compared to the isotype controls. Anti-TfR mAb suppressed IL-2, interferon-γ/(IFNγ), IL-10, and IL-12 p40 mRNA expression, but had no effect on IL-4, IL-12 p35, and IL-15 mRNA expression. In conclusion, anti- TfR mAb prolongs allograft survival, suppresses T cell function, and alters IL-2, IL-10, IL-12 p40, and IFN-γ mRNA expression. These data suggest that the downregulation in IL-12 mRNA by anti-TfR mAb may prevent the development of T helper cells, thereby promoting graft survival and altering cell- mediated immune responses. The partial effect by anti-TfR mAb on cytokine mRNA expression may be due to other contributing factors such as costimulation.