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

Abstract

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.