Superantigen-induced human CD4+ helper/killer T cell phenomenon. Selective induction of Th1 helper/killer T cells and application to tumor immunotherapy.
Human CD4+ T cells activated with staphylococcal enterotoxin A (SEA) were fractionated by Percoll discontinuous density gradient centrifugation to enrich SEA-reactive CD4+ T cells. The SEA-reactive CD4+ T cells showed significant cytotoxicity, so-called superantigen-dependent cell-mediated cytotoxicity, against SEA-coated class II-positive tumor cells. During lysis of SEA-coated tumor cells, SEA-reactive CD4+ T cells produced high levels of IL-2 and IFN-gamma but not IL-4 in an Ag-specific manner. The skewing of human CD4+ T cells to Th1-type helper/killer T cells was also demonstrated when SEA-reactive CD4+V beta 5.3+ clonal T cells were cultured with SEA, but not with PHA or OKT3 mAb. Interestingly, the generation of SEA-reactive helper/killer T cells was negatively regulated by IL-4, but up-regulated by IL-12. The SEA-reactive CD4+ helper/killer T cells were able to generate from PBMC of tumor patients and could be expanded to 10(9) levels in a 7-day culture. The SEA-reactive CD4+ helper/killer T cells were specifically targeted to c-erbB-2 positive human colon cancer cells using SEA-conjugated-anti-c-erbB-2 mAb. These results initially demonstrated that SEA-activated human CD4+ T cells are a Th1 type of Th cell that has both helper and killer functions which may be useful for adoptive tumor immunotherapy in combination with SEA-conjugated antitumor mAb.
Department of Surgery, Tokai University School of Medicine, Isehara, Japan.
S
S
Kuge
Y
Y
Miura
Y
Y
Nakamura
T
T
Mitomi
S
S
Habu
T
T
Nishimura
D000911:Antibodies, Monoclonal / Q000276:immunology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D004768:Enterotoxins / Q000276:immunology; D000949:Histocompatibility Antigens Class II; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D018089:Superantigens / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D004768:Enterotoxins; D000949:Histocompatibility Antigens Class II; D007371:Interferon-gamma; D007376:Interleukin-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D018089:Superantigens; C026066:enterotoxin A, Staphylococcal