TRANSPLANTATION CD8 but not CD4 T cells require cognate interactions with target tissues to mediate GVHD across only minor H antigens, whereas both CD4 and CD8 T cells require direct leukemic contact to mediate GVL

Whether T-cell antigen receptors (TCR) on donor T cells require direct interactions with major histocompatibility complex class I or class II (MHCI/MHCII) molecules on target cells to mediate graftversus-host disease (GVHD) and graftversus-leukemia (GVL) is a fundamental question in allogeneic stem-cell transplantation (alloSCT). In MHC-mismatched mouse models, these contacts were not required for GVHD. However, this conclusion may not apply to MHC-matched, multiple minor histocompatibility antigenmismatched alloSCT, the most common type performed clinically. To address this, we used wild-type (wt)3MHCI / or wt3MHCII / bone marrow chimeras as recipients in GVHD experiments. For GVL experiments, we used MHCI / or MHCII / chronic-phase CML cells created by expressing the BCR-ABL cDNA in bone marrow from MHCI / or MHCII / mice. TCR/MHCI contact was obligatory for both CD8-mediated GVHD and GVL. In contrast, CD4 cells induced GVHD in wt3MHCII / chimeras, whereas MHCII / mCP-CML was GVL-resistant. Donor CD4 cells infiltrated affected skin and bowel in wt3MHCII / recipients, indicating that they mediated GVHD by acting locally. Thus, CD4 cells use distinct effector mechanisms in GVHD and GVL: direct cytolytic action is required for GVL but not for GVHD. If these noncytolytic pathways can be inhibited, then GVHD might be ameliorated while preserving GVL. (Blood. 2008;111:3884-3892)