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 (1degrees). In vivo anti-tumor immunity and in vitro cytotoxicity of 1degrees Tc2 memory effector cells were highly protective comparably to 1degrees Tc1, but they secreted high level of IFNgamma as well as IL 4 and IL 5. Moreover, memory cells obtained again from tumor-protected mice by either 1degrees Tc1 or Tc2 transfer showed indistinguishable, Tc1-like, cytokine profiles. These results strongly suggest that 1degrees 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 (2degrees) markedly reduced secretion of IFNgamma (by 94%) and in vivo tumor protection (by 83%). Tertiary (3degrees) and further stimulation completely abrogated both of tumor protective activity and IFNgamma 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 1degrees Tc2 cells were trans-differentiated to Tc1 during secondary stimulation, 2 of 6 cultures recovered tumor protective activity concomitantly with IFNgamma secretion, indicating that repeated stimulation does not deteriorate tumor protective activity of 2degrees Tc2 cells. Collectively, these data demonstrate that highly committed Tc2 cells are ineffective in tumor protection. (C) 2004 Elsevier B.V. All rights reserved.