Characterization of tumor-infiltrating CD4+ T cells as Th1 cells based on lymphokine secretion and functional properties.
Recent studies have subdivided the Th cells into mutually exclusive Th1 subset producing IL-2 and IFN-gamma and Th2 cells producing IL-4 and IL-5. The relative role played by these two subsets in the antitumor immunity is not clear. We earlier demonstrated that treatment of C57BL/6 mice bearing a syngeneic Ia- T cell lymphoma, LSA, with 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) resulted in 90 to 100% survival of the mice. Furthermore, host's T cell responses were critical for successful BCNU-mediated cures. In our study we observed that immediately after BCNU treatment, there was a dramatic increase in the percentage of CD4+ T cells at the site of tumor growth in the peritoneal cavity. The percentage of CD4+ T cells increased from approximately 3 to 4% found in normal or tumor-bearing mice to approximately 41% in BCNU-treated tumor-bearing mice. The percentage of CD8+ T cells also increased although to a lesser degree. Also, these alterations were primarily restricted to the site of tumor-growth inasmuch as they were not seen in the thymus and were less pronounced in the spleen. The tumor-infiltrating CD4+ T cells obtained after BCNU-treatment, when further characterized, were found to secrete only IL-2 and IFN-gamma but not IL-4, after tumor-specific stimulation. Furthermore, the supernatants from LSA-activated CD4+ T cell cultures failed to provide help to the B cells but were able to activate the macrophages to inhibit the tumor cell proliferation. The CD4+ T cells when adoptively transferred could also protect the nude mice from LSA tumor challenge and induced tumor-specific delayed-type hypersensitivity reaction. Together our data suggest that in the LSA tumor model, the tumor-infiltrating CD4+ T cells have the properties of Th1 cells and these cells can mediate tumor-rejection independent of the CD8+ T cells by activating the macrophages.
Nagarkatti
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Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg 24061.
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Nagarkatti
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D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016827:CD8 Antigens; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008222:Lymphokines / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000276:immunology*; D010529:Peritoneal Cavity / Q000166:cytology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
D000945:Antigens, Differentiation, T-Lymphocyte; D016827:CD8 Antigens; D007376:Interleukin-2; D008222:Lymphokines; D015847:Interleukin-4; D007371:Interferon-gamma