The critical role of mouse CD4+cells in the rejection of highly disparate xenogeneic pig thymus grafts

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Abstract
Long‐term survival of fetal pig thymus (FP THY) grafts and efficient repopulation of mouse CD4+T cells is achieved in thymectomized (ATX) B6 mice that receive T and NK cell depletion by injection of a cocktail of mAbs (GK1.5, 2.43, 30‐H12, and PK136) and fetal pig thymus/liver (FP THY/LIV) grafts. The requirement for each mAb in this conditioning regimen in order to avoid the rejection of FP THY grafts has not yet been defined. In our present studies, CD4 cell‐depleted ATX B6 mice and euthymic MHC class II‐deficient (IIKO) mice were employed to investigate the role of mouse CD4+cells in the rejection of FP THY grafts in vivo. After grafting FP THY/LIV to CD4+cell‐depleted ATX B6 mice, efficient repopulation of mouse CD4+T cells was observed in the periphery. However, only two of four mice had remaining FP THY grafts by 17 weeks post‐implantation, and these were of poor quality, whereas four of four T and NK cell‐depleted ATX B6 mice had well‐developed FP THY grafts. Furthermore, three of four FP THY/LIV‐grafted, CD4+cell‐depleted ATX B6 mice rejected donor MHC‐matched pig skin grafts. In contrast, three of three FP THY/LIV grafted, T and NK cell‐depleted, ATX B6 mice accepted donor MHC‐matched pig skin grafts, suggesting that optimal tolerance to xenogeneic pig antigens was not achieved in mice conditioned only with anti‐CD4 mAb. ATX B6 mice treated with only anti‐CD8 mAb rejected FP THY completely by 6 weeks post‐grafting, a time when CD4+cell‐depleted ATX B6 mice had well‐vascularized FP THY grafts. In addition, when euthymic IIKO mice were pre‐treated with the standard conditioning regimen that includes four different mAbs, FP THY grafts survived and supported the repopulation of mouse CD4+T cells in the periphery, while high levels of mouse CD8+T cells developed in host thymi. These studies suggest that mouse CD4+T cells play a critical role in the acute rejection of xenogeneic FP THY grafts. Without help from CD4+cells, mouse CD8+cells, NK, NK/T, and TCR(γ/δ)+T cells do not mediate acute rejection of FP THY grafts. Furthermore, our results suggest that other cell subsets besides CD4+T cells play a role in the delayed rejection of highly disparate xenogeneic FP THY grafts.