FKBP5 isoforms shape immune pathways related to tumor tolerance

Area of Science:

• Immunology
• Molecular Biology
• Cancer Research

Background:

• FKBP51 is an immunophilin regulating crucial cellular pathways.
• Alternative splicing generates FKBP51s, a shorter isoform lacking protein interaction domains.
• Splicing of FKBP5 impacts T lymphocyte expansion and immune response tuning.

Purpose of the Study:

• To investigate the impact of FKBP51 splicing on immune homeostasis and antitumor responses.
• To determine the functional role of FKBP51 isoforms in lymphocyte activation and effector functions.

Main Methods:

• Generation of a knock-in mouse model (huFKBP5) expressing only full-length human FKBP51.
• Assessment of immune homeostasis, fertility, and lymphoid infiltrates in homozygous and heterozygous mice.
• Evaluation of antitumor response in a syngeneic melanoma model using huFKBP5+/- mice.
• Demonstration of species-wide functional equivalence of FKBP51 using synthetic mRNAs.

Main Results:

• Homozygous huFKBP5+/+ mice exhibited impaired immune homeostasis, infertility, and lymphoid infiltrates.
• HuFKBP5+/- mice showed potent antitumor responses with reduced tumor growth and increased lymphocyte infiltration.
• Elevated cytotoxic markers and specific chemokine receptors (CCR7, CXCR5) were observed on tumor-infiltrating lymphocytes.
• FKBP51s isoform acted as a dominant-negative regulator of murine lymphocyte effector functions.

Conclusions:

• Inhibiting FKBP51 splicing preserves lymphocyte effector activity and prevents exhaustion.
• Blocking FKBP51 splicing enhances antitumor immunity and reduces tumor tolerance.
• FKBP51 splicing represents a critical regulatory mechanism in immune responses and cancer.