Sialoadhesin-positive host macrophages play an essential role in graft-versus-leukemia reactivity in mice.
We recently established an effective immune T-cell-mediated graft-versus-leukemia (GVL) murine model system in which complete tumor remissions were achievable even in advanced metastasized cancer. We now describe that this T-cell-mediated therapy is dependent on host macrophages expressing the lymphocyte adhesion molecule sialoadhesin (Sn). Depletion of Kupffer cells in tumor-bearing mice during adoptive immunotherapy (ADI) or the treatment of these animals with anti-Sn monoclonal antibodies led to complete or partial inhibition of the immune T-cell-mediated therapeutic effect. Furthermore, Sn+ host macrophages in livers formed clusters during ADI with donor CD8 T cells. To test for a possible antigen presentation function of these macrophages, we used as an in vitro model the antigen beta-galactosidase for which a dominant major histocompatibility complex (MHC) class I Ld-restricted peptide epitope is known to be recognized by specific CD8 cytotoxic T lymphocytes (CTL). We demonstrate that purified Sn+ macrophages can process exogenous beta-galactosidase and stimulate MHC class I peptide-restricted CTL responses. Thus, Sn+ macrophages, which are significantly increased in the liver after ADI, may process tumor-derived proteins via the MHC class I pathway as well as via the MHC class II pathway, as shown previously, and present respective peptide epitopes to CD8 as well as to CD4 immune T cells, respectively. The synergistic interactions observed before between immune CD4 and CD8 T cells during ADI could thus occur in the observed clusters with Sn+ host macrophages.
Müerköster
S
S
Division of Cellular Immunology, Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany.
Rocha
M
M
Crocker
P R
PR
Schirrmacher
V
V
Umansky
V
V
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000032:analysis; D002452:Cell Count; D020350:Graft vs Tumor Effect; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D016219:Immunotherapy, Adoptive; D007728:Kupffer Cells / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000276:immunology / Q000628:therapy*; D008264:Macrophages / Q000737:chemistry* / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D011971:Receptors, Immunologic / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000502:physiology; D063267:Sialic Acid Binding Ig-like Lectin 1; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D063267:Sialic Acid Binding Ig-like Lectin 1; C571167:Siglec1 protein, mouse