Functional analysis of immunological mechanisms following mouse liver transplantation

Aims: Mouse liver transplantation (MLTx) results in spontaneous allospecific tolerance induction; however, the mechanisms orchestrating this phenomenon are not identified. For this study characterizes the magnitude, phenotype, and persistence of alloreactive T cell responses. Methods: Balb/C livers were transplanted into B10 recipients. The alloreactive T-cell response was studied by 1) adoptively transferred transgenic alloreactive T cells, 2) in vivo MLR, for the endogenous alloreactive T cell response, and 3) in vivo cytotoxicity assays. Results: Adoptive transfer of TCR-tg donor-reactive T cells with direct and indirect specificity, showed a more robust immune response compared to skin or heart Tx. Large numbers of donor-reactive T cells were detectable 21 days following MLTx, when the recipient mice were already tolerant to allospecific skin grafts. In vivo MLR of the endogenous alloreactive T cell population confirmed the persistence of fully functional endogenous effector T cells at Day 21 and up to 250 days post-MLTx. Donor-specific cytotoxic CD8+ T cells were significantly reduced compared to third-party-reactive CD8 T cells 21 days after MLTx. Despite the low frequency of donor-reactive CD8+ T cells, the ability to selectively eliminate allospecific target cells was preserved in an in vivo CTL assay. In addition, splenocytes from day 90 post-MLTx mice were found to be capable of rejecting donor skin grafts when transferred into Rag1-/- hosts. Conclusion: This study demonstrates the magnitude and persistence of donor-reactive T cell responses after MLTx in new detail and strongly opposes either deletional tolerance or regulatory T cell induction as relevant mechanisms for tolerance induction following MLTx. The deletion of effector CD8+ T cells may help to protect liver allografts, however, given the preserved functional capacity of this T cell compartment this mechanism is unlikely to entirely account for tolerance induction following MLTx.

T-cell activation - direct/indirect allorecognition - mouse liver transplantation - tolerance induction