Identification of progenitor CD4 T cells that support response to chronic antigen

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Abstract Durable immune response by both CD4 and CD8 T cells is required for the control of chronic infection or tumors. In the past few years, multiple independent studies have identified a subset of progenitor-like or stem- like TCF-1+ PD-1+ CD8 T cells in both chronic viral infections and tumors. These progenitor CD8 T cells continue generating new effector CD8 T cells to support long-term CD8 T cell responses to persisting antigens (Ags). They are also capable of eliciting robust effector responses by the immune checkpoint blockade targeting the PD-1 to PD-L1 interaction. However, it remains unknown how CD4 T cell responses to persistent Ag are maintained, or whether a specialized subset of progenitor-like CD4 T cells equivalent to TCF-1+ progenitor CD8 T cells exists to support the durability of CD4 T cell response or respond to the PD-1 blockade. We have found that the transcription factor BCL6 is essential for the durable CD4 T cell effector response to chronic LCMV infection, implying that an analogous progenitor CD4 T cells are present in the face of chronic antigen stimulation. We propose to identify such a CD4 T cell population and conduct the initial characterization of the unique CD4 T cell subset.