T-Cell Activation, Proliferation, and Memory After Cardiac Transplantation In Vivo

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Abstract
To study the response of alloantigen (H2Kb)-specific T cells to a H2b+ cardiac allograft in vivo. The response of T cells to alloantigen has been well characterized in vitro but has proved more difficult to assess in vivo. The aim of these experiments was to develop a model of T-cell-mediated rejection where the response of T cells after transplantation of a cardiac allograft could be followed in vivo. Purified CD8+ T cells from H2Kb-specific TCR transgenic mice (BM3; H2k) were adoptively transferred into thymectomized, T-cell-depleted CBA/Ca (H2k) mice. These mice were then transplanted with a H2Kb+ cardiac allograft. Using four-color flow cytometry, the proliferative response, modulation of activation markers, and potential cytokine production of the H2Kb-specific T cells was assessed after transplantation. Consistent rejection of H2Kb+ cardiac allografts required the transfer of at least 6 × 106 CD8+ H2Kb-specific T cells. Short-term analyses revealed that the transgenic-TCR+/CD8+ T cells proliferated and became activated after transplantation of an H2Kb+ cardiac allograft. Fifty days after transplantation, the transgenic-TCR+/CD8+ T cells remained readily detectable, bore a predominantly memory phenotype (CD44hi), and rapidly produced interleukin 2 and interferongamma on in vitro restimulation. These data show that the activation of alloantigen-specific T cells can be followed in vivo in short-term and long-term experiments, thereby providing a unique opportunity to study the mechanisms by which T cells respond to allografts in vivo.