Abstract Body (Do not enter title and authors here): Background：
Antigen presentation to CD4+ T cells plays a critical role in heart failure (HF). Dipeptidyl peptidase 4 (DPP4) has been shown to promote the activation of T lymphocytes. This study aims to investigate the role of DPP4 in antigen presentation in pressure overload-induced HF.

Methods:
To examine the role of DPP4 in antigen presentation during HF, we tested the recruitment and function of dendritic cells (DCs) in transverse aortic constriction (TAC)-induced HF mice. To further investigate, we generated DPP4 knockout mice and induced bone marrow-derived dendritic cells (BMDCs) in vitro. BMDCs were then adoptively transferred into OT-II mice, whose DCs require specific exogenous ovalbumin loading to activate CD4+ T cells. RNA-Seq analysis was performed to elucidate the mechanisms by which DPP4 affects the function of DCs.

Results:
We observed an increased quantity of DCs in the hearts and mediastinal lymph nodes of TAC mice, accompanied by elevated expression of DPP4. These DCs exhibited enhanced antigen-presenting abilities, resulting in increased activation of CD4+ T cells. DPP4 knockout suppressed DC maturation and attenuated their antigen-presenting capabilities. We found that OT-II mice subjected to TAC showed preserved cardiac function compared to wild-type (WT) mice. However, OT-II mice that received adoptive transfer of DPP4+/+ BMDCs exhibited worse cardiac function compared to those receiving DPP4-/- BMDCs, indicating that DPP4 in DCs contributes to HF progression. RNA-Seq analysis indicated that DPP4 in DCs influenced the T cell receptor signaling pathway and T cell differentiation. Mechanistically, DPP4 was found to inhibit the E3 ubiquitin ligase MARCH1 from binding to MHCII, thereby stabilizing MHCII through preventing its ubiquitin-dependent degradation in DCs.

Conclusion:
This study elucidates the significance of DPP4 in enhancing antigen presentation during heart failure. We propose that DPP4 represents a potential therapeutic target for heart failure.