Interleukin 3 enhances development of tumor-reactive cytotoxic cells by a CD4-dependent mechanism.
We investigated the effects that mouse interleukin 3 (IL-3), in comparison to mouse IL-2, has on the generation of cytotoxic effectors capable of killing line 1 tumor cells. These potent immunological mediators were delivered locally using gene transfection, rather than systemically, to the tumor site. We created line 1 transfectants that express high levels of IL-3 (3750 units/ml) or IL-2 (200 units/ml) by driving transcription from the beta-actin promoter. These levels of expression significantly enhanced tumor rejection in syngeneic mice. Tumor-infiltrating lymphocytes purified from IL-3 or IL-2 transfected tumors showed a dramatically enhanced cytotoxic response to parental line 1 targets. Also, IL-2, but not IL-3, expression enhanced the nonspecific lysis of YAC-1 cells. In vivo depletion of CD8+ cells with monoclonal antibody 2.43 abrogated the generation of cytotoxic effectors in both cases. Interestingly, depletion of CD4+ cells with monoclonal antibody GK1.5 abrogated the IL-3-mediated cytotoxic response but not the IL-2-mediated response. In vivo depletion of CD4+ or CD8+ cells abrogated the effect IL-3 had on reducing tumorigenicity. Reverse polymerase chain reaction analysis demonstrates that IL-3 transfected tumors, when compared to untransfected tumors, express increased levels of IL-2 and IL-4 mRNA. These results strongly suggest that IL-3, unlike IL-2, works to generate cytotoxic effectors by a mechanism that requires CD4+ cells.
Pulaski
B A
BA
Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, New York 14642.
McAdam
A J
AJ
Hutter
E K
EK
Biggar
S
S
Lord
E M
EM
Frelinger
J G
JG
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016827:CD8 Antigens / Q000032:analysis; D002277:Carcinoma / Q000276:immunology* / Q000473:pathology; D003602:Cytotoxicity, Immunologic; D015870:Gene Expression; D007111:Immunity, Cellular; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000235:genetics; D007377:Interleukin-3 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000235:genetics; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D016827:CD8 Antigens; D007376:Interleukin-2; D007377:Interleukin-3; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D015847:Interleukin-4