CD4 Cytotoxic T cells play a critical role in anti-tumor protection

Abstract

Abstract The CD4 T cell lineage is established in the thymus by the transcription factor, ThPOK. In the periphery, ThPOK maintains the CD4 T helper commitment and allows the differentiation to different helper fates in response to stimulation with cognate antigens. We demonstrated that in the intestine, chronic stimulation of CD4 T cells results in the loss of ThPOK expression leading to the reprogramming of the T helper cells to cytotoxic T lymphocytes (CTL), expressing notably CD8 T cells attributes. Continuous activation in a non-immunogenic environment is also a hallmark of tumor progression. We investigated if the tumor environment supports the generation of CD4 CTL and moreover if they play essential roles in anti-tumor protection. Using the well-defined melanoma B16 model, we observed that CD4 T cells responding to the tumor uniquely lose ThPOK expression. To address the importance of the CD4 CTL in the tumor immune surveillance, we engineered two unique mouse models, in which either all the CD4 T cells are forced to reprogram to CTL or else, prevented from reprogramming to CTL. Using these models, we observed that the forced CD4 CTL eradicate melanoma cells, whereas the CD4 cells which cannot lose ThPOK and reprogram to CTL are ineffective against the tumor growth. These findings underscore the importance of CD4 CTL reprogramming in protective immunity. Finally, we developed a culture system to induce the reprograming of CD4 Th to CTL in vitro. We injected in vitro-generated CD4 CTL alone or with a co-transfer of CD8 T cells into Rag deficient hosts bearing tumor. As compared to the transfer of the CD4 CTL or CD8 CTL alone, the cooperation of the cytotoxic effector cells displayed a strong synergized effect on long term protection against tumor growth.