Committed memory effector type 2 cytotoxic T (Tc2) cells are ineffective in protective anti-tumor immunity

Cytotoxic CD8 ⁺ T cells (Tc) are a major effector cell population in protection against tumor growth and classified into Tc1 or Tc2 based on their cytokine-secreting profiles. However, their relative tumor protective roles remain undefined. In the present study, CD8 ⁺ memory T cells were obtained from mice given with CT26-IL 12 and tumor-specific Tc1 and Tc2 cells were induced by in vitro primary stimulation (1°). In vivo anti-tumor immunity and in vitro cytotoxicity of 1°Tc2 memory effector cells were highly protective comparably to 1°Tc1, but they secreted high level of IFNγ as well as IL 4 and IL 5. Moreover, memory cells obtained again from tumor-protected mice by either 1°Tc1 or Tc2 transfer showed indistinguishable, Tc1-like, cytokine profiles. These results strongly suggest that 1°Tc2 cells are insufficiently polarized. Tc2 memory effector cells were therefore examined for their transitional anti-tumor activity during consecutive stimulation until Th2 commitment. Secondary stimulation (2°) markedly reduced secretion of IFNγ (by 94%) and in vivo tumor protection (by 83%). Tertiary (3°) and further stimulation completely abrogated both of tumor protective activity and IFNγ secretion of Tc2 cells. This progressive loss of activity following repeated stimulation was accompanied by a reduction of in vitro cytotoxicity to CT26 tumor cells. In addition, when 1°Tc2 cells were trans-differentiated to Tc1 during secondary stimulation, 2 of 6 cultures recovered tumor protective activity concomitantly with IFNγ secretion, indicating that repeated stimulation does not deteriorate tumor protective activity of 2°Tc2 cells. Collectively, these data demonstrate that highly committed Tc2 cells are ineffective in tumor protection.