Role of IL-2, IL-4 and IL-6 in the growth and differentiation of tumor-specific CD4+ T helper and CD8+ T cytotoxic cells.
We have earlier observed that 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU), a chemotherapeutic drug, cured 90-100% of mice bearing a syngeneic Ia- T-cell lymphoma (LSA) and furthermore, 100% of the BCNU-cured mice could reject homologous tumor rechallenge. In the present study, purified CD4+ and CD8+ T cells isolated from BCNU-cured mice were used to investigate the mechanism by which such T cells recognized and responded to the tumor-specific antigens. The responsiveness of CD4+ T cells to LSA was dependent on processing and presentation of tumor-specific antigens by syngenic Ia+ splenic antigen-presenting cells (APC). Such activated CD4+ T cells endogenously produced IL-2 but not IL-4 and only IL-2 acted as an autocrine growth factor inasmuch as anti-IL-2 receptor antibodies but not anti-IL-4 antibodies inhibited the CD4+ T cell proliferation. In contrast, the CD8+ T cells failed to produce endogenous growth factors when stimulated with LSA alone or with LSA plus APC, and therefore failed to proliferate. However, in the presence of exogenous recombinant IL-2 (rIL-2), CD8+ T cells could proliferate directly in response to LSA-stimulation, even in the absence of APC. Addition of exogenous rIL-4 alone to cultures induced CD4+ but not CD8+ T cells to proliferate. However, rIL-4 in the presence of rIL-2, could synergize and induce tumor-specific proliferation of CD8+ cells. These data suggested that for IL-4 to act as a T-cell growth factor, the presence of IL-2 was essential, either in the form of endogenously secreted IL-2 (CD4+ T cells) or exogenous IL-2 (for CD8+ T cells). In contrast to rIL-2 and rIL-4, rIL-6 failed to induce growth when used alone or in combination with rIL-2 or rIL-4. Furthermore, when tested individually, only rIL-2 but not rIL-4 or rIL-6 could support the cytotoxic differentiation of CD8+ T cells. The present study suggests that the early events in responsiveness to LSA tumor may involve activation of the IL-2-producing Th1 subpopulation of CD4+ helper cells which in turn activate IL-2 dependent CD8+ cytotoxic T cells. IL-4 if produced subsequently, may act synergistically with IL-2 to promote the growth of CD4+ and CD8+ T cells.
Selvan
R S
RS
Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg 24061.
Nagarkatti
P S
PS
Nagarkatti
M
M
D000818:Animals; D000911:Antibodies, Monoclonal; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D016827:CD8 Antigens; D002330:Carmustine / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002469:Cell Separation; D002738:Chloroquine / Q000494:pharmacology; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D008223:Lymphoma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D016827:CD8 Antigens; D007376:Interleukin-2; D015850:Interleukin-6; D015847:Interleukin-4; D002738:Chloroquine; D002330:Carmustine