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)‐l‐nitrosourea (BCNU), a chemotherapeutic drug, cured 90–100% of mice bearing a syngeneic la− 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 syngeneic la+ 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. Copyright © 1990 Wiley‐Liss, Inc., A Wiley Company