The role of CD8 and CD4 T cells in intestinal allograft rejection - A comparison of monoclonal antibody-treated and knockout mice

Background. The relative contribution of CD8 and CD4 T cells to allograft r ejection remains an unresolved issue. Experimental results suggest that the relative importance of these T-cell subsets may vary depending on the mode l used and the organ studied. We have previously shown that treatment of mu rine recipients of intestinal allografts with a depleting anti-CD8 or a dep leting anti-CDC monoclonal antibody (mAb) significantly inhibited allograft rejection. This study was undertaken to further examine the contribution o f CD8 and CD4 T cells to the rejection of intestinal allografts. Methods. Intestinal allografts from B6C3F1/J (C57BL/6 x C3H/HeJ) mice were transplanted into C57BL/6 recipients. Recipient groups included mice with a n acquired deficiency in CD8 or CD4 T cells caused by treatment with deplet ing mAb or mice genetically deficient in CD8 or CD4 T cells as a result of disruption of the genes encoding major histocompatibility complex (MHC) cla ss I, MHC class II, CD8, or CD4, In all cases, rejection was assessed histo logically at predetermined time points. In some recipient groups, graft fun ction was also assessed using a maltose absorption assay. Results. Rejection, assessed between days 10 and 28 after transplantation, was significantly inhibited in mice deficient in CDS or CD4 T cells after t reatment with depleting mAb. In contrast, mice genetically deficient in eit her CD8 T cells (MHC class I or CD8 knockouts) or CD4 T cells (MHC class II or CD4 knockouts) rejected intestinal allografts promptly. Both histologic and functional evaluation of anti-CDS mAb-treated mice on day 60 showed th at the inhibition of rejection persisted even after the return of a substan tial number of CD8 T cells. Although intestinal allografts from anti-CD8 mA b-treated mice displayed little to no evidence of rejection on day 60 after transplantation, these mice were able to reject both donor and third-party skin grafts. Conclusions. These results demonstrate that the inhibition of intestinal al lograft rejection associated with mAb treatment is not attributable solely to depletion of CD8 or CD4 T cells. Furthermore, anti-CD8 mAb administratio n did not induce donor-specific tolerance or cause nonspecific immune suppr ession, as indicated by the skin-grafting experiments. Our findings suggest that at least some depleting mAbs mediate their protective effect on allog raft rejection via an alternative mechanism such as the induction of a regu latory cell population(s).