FKBP5 isoforms shape immune pathways related to tumor tolerance

FKBP51 is a multifunctional immunophilin that regulates key cellular pathways, including NF-κB signaling, AKT activation, and steroid receptor trafficking. Alternative splicing of the FKBP5 gene generates a shorter isoform, FKBP51s, lacking the C-terminal TPR domain mediating protein‒protein interactions. Previous studies support the hypothesis that splicing of the FKBP5 gene underpins the mechanisms crucial for establishing control over T lymphocyte expansion and that the balance between the canonical and spliced isoforms could be pivotal in the immune system's capacity to finely tune the intensity and span of the immune response.To investigate the impact of FKBP51 splicing, we generated a knock-in mouse model (huFKBP5) expressing only the full-length human FKBP51 isoform, thereby ablating all splice variants. While the heterozygous animals were viable and fertile, the homozygous huFKBP5^+/+ mice presented a sub-Mendelian frequency, infertility, and widespread lymphoid infiltrates, suggesting impaired immune homeostasis. In a syngeneic melanoma model, huFKBP5^+/- mice presented a potent antitumor response characterized by reduced tumor growth, increased lymphocyte infiltration, elevated levels of cytotoxic markers (perforin, Bax, cleaved caspase-3 and -7, gasderminE), and the upregulation of CCR7 and CXCR5 on tumor-infiltrating lymphocytes. By employing synthetic mRNAs, we demonstrated that FKBP51 retains functional equivalence across species in driving lymphocyte activation. The FKBP51s isoform functions as a dominant-negative regulator of murine lymphocyte effector functions. These findings support the conclusion that inhibiting FKBP51 splicing preserves lymphocyte effector activity and prevents their transition toward resting or exhausted states. In the tumor context, this translates into a heightened antitumor immune response and a reduction in tumor tolerance.