Graft-versus-leukemia reactivity involves cluster formation between superantigen-reactive donor T lymphocytes and host macrophages.
T-cell-mediated antitumor effects play an important role clinically in allogeneic graft-versus-leukemia (GvL) reactivity, whereas T-cell-mediated antihost effects are associated with a risk of developing graft-versus-host (GvH) disease. GvL and GvH were compared in an animal tumor model system after the systemic transfer of allogeneic antitumor immune T lymphocytes from B10.D2 [H-2d; minor lymphocyte-stimulating antigen (Mls)b] mice into ESb-MP tumor-bearing or normal DBA/2 (H-2d; Mls(a)) mice. Here we demonstrate that this T-cell-mediated therapy involves the formation of clusters of donor CD4 and CD8 T cells with host macrophages, in particular, with a subpopulation expressing the lymphocyte adhesion molecule sialoadhesin. DBA/2 mice and the derived tumor ESb-MP express viral superantigen 7 (Mls(a)), an endogenous viral superantigen that is absent from B10.D2 mice. To test the contribution of viral superantigen 7-reactive Vbeta6 donor T cells in the GvL-mediated eradication of liver metastases, we performed immunohistological and transmission electron microscopy studies. Vbeta6+ CD4 and CD8 T cells from B10.D2 donors formed tight clusters with host sialoadhesin-positive macrophages, and transmission electron microscopy pictures revealed direct membrane-membrane interactions between T cells and macrophages. Clusters were more abundant and consisted of more cells in tumor-bearing hosts (GvL model) than in non-tumor-bearing hosts (GvH model). In addition, Vbeta6 T cells within the clusters showed a strong proliferation activity, indicating stimulation. Moreover, in an in vitro tumor cytostasis assay, primed as well as nonprimed purified Vbeta6 T cells from donor mice were able to inhibit the proliferation of superantigen-expressing ESb-MP lymphoma cells. This suggests that the transferred superantigen-reactive Vbeta6 T cells contribute to the eradication of metastases. The observed cell clusters might be sites for antigen presentation and the activation of tumor-reactive T cells.
Müerköster
S
S
Deutsches Krebsforschungszentrum, Abteilung Zelluläre Immunologie, FSP Tummorimmunologie, Heidelberg, Germany.
Wachowski
O
O
Zerban
H
H
Schirrmacher
V
V
Umansky
V
V
Rocha
M
M
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division; D016207:Cytokines / Q000096:biosynthesis; D006086:Graft vs Host Disease / Q000473:pathology; D020350:Graft vs Tumor Effect; D016219:Immunotherapy, Adoptive; D008113:Liver Neoplasms / Q000556:secondary; D008223:Lymphoma / Q000473:pathology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008811:Mice, Inbred DBA; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D013154:Spleen / Q000378:metabolism; D018089:Superantigens / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation
D016207:Cytokines; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018089:Superantigens; C081278:T cell receptor Vbeta6.7a, human