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 …

C Matte-Martone, J Liu, D Jain, J McNiff… - Blood, The Journal …, 2008 - ashpublications.org
C Matte-Martone, J Liu, D Jain, J McNiff, WD Shlomchik
Blood, The Journal of the American Society of Hematology, 2008ashpublications.org
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 graft-versus-host disease (GVHD) and graft-versus-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 antigen-mismatched alloSCT …
Abstract
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 graft-versus-host disease (GVHD) and graft-versus-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 antigen-mismatched alloSCT, the most common type performed clinically. To address this, we used wild-type (wt)→MHCI−/− or wt→MHCII−/− 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 wt→MHCII−/− chimeras, whereas MHCII−/− mCP-CML was GVL-resistant. Donor CD4 cells infiltrated affected skin and bowel in wt→MHCII−/− 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.
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