title: 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.
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.
authors.affiliation: Section of Medical Oncology, Cancer Center, Yale University School of Medicine, New Haven, CT 06520-8032, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Matte-Martone
authors.forename: Jinli
authors.initials: J
authors.lastname: Liu
authors.forename: Dhanpat
authors.initials: D
authors.lastname: Jain
authors.forename: Jennifer
authors.initials: J
authors.lastname: McNiff
authors.forename: Warren D
authors.initials: WD
authors.lastname: Shlomchik
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D051379:Mice; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D033581:Stem Cell Transplantation; D018183:Transplantation Chimera / Q000235:genetics / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D015778:Minor Histocompatibility Antigens; D011948:Receptors, Antigen, T-Cell