The BMP-KLF3 circuit promotes resilient programming in CD8+ T cells during chronic infection and cancer

Introduction/Rationale: Cytotoxic CD8+ T cells progressively lose function and become terminally exhausted during chronic infections and cancer. We previously showed that chronic antigen exposure plus TGFβ1 signals drive epigenetically imprinted terminal exhaustion programs in CD8 T cells. In contrast, activating bone morphogenetic protein (BMP) signaling together with TGFβ1 receptor blockade restores functional programming and antitumor activity in CD8 T cells. Moreover, BMP activation recovers expression of the Krüppel-like factor 3 (KLF3) transcription factor, which is uniquely expressed in functional CD8 T cells during chronic infection and cancer. However, the role of BMP-KLF3 axis in reprogramming exhausted T cells remains unclear. Identifying programmable pathways that prevent terminal exhaustion is critical for improving the efficacy of T cell-based immunotherapies.

Methods: To assess the role of BMP-driven KLF3 in CD8 T cell programming, we co-adoptively transferred congenically distinct control and KLF3-overexpressing (OE) P14 CD8+ T cells into mice, followed by chronic LCMV infection or gp33-expressing melanoma. Functional, transcriptional, and epigenetic analyses were performed to identify the molecular circuits regulated by BMP-KLF3 pathway.

Results: We show that BMP activation prevented epigenetic silencing of KLF3 in chronically stimulated CD8 T cells. Importantly, induced expression of KLF3 (OE) reprogrammed exhausted T cells by enhancing their fitness and proliferation capacity during chronic infection, as well as promoting their cytotoxicity and tumor control in vivo.

Conclusion: Our findings reveal a novel molecular pathway in which BMP signaling drives KLF3, a key transcriptional mediator that programs resilient CD8+ T cell responses during chronic infection and cancer. Our findings reveal a promising approach to enhance responses to adoptive T cell-based immunotherapies.