FKBP5 splicing concurs to Treg differentiation of Tconv cells

FKBP51 (FKBP5 gene) is an immunophilin physiologically expressed by immune cells. Thanks to its scaffold and isomerase activity supporting IKK complex assembly and function, FKBP51 plays a relevant role in NF-κB activation. Recently, we identified a splicing isoform, shorter than the canonical one, termed FKBP51s. FKBP51s acts as a PD-L1 foldase, assisting to protein maturation and expression on plasma membrane. Particularly, FKBP51s was firstly identified in TILs and PBMCs of melanoma patients. In these patients, FKBP51s marked a subset of Tregs with an increased phospho-mTOR and Ki67 expression. Logistic regression analysis suggested that FKBP51sTreg is a valuable element which predicts the probability of response to ipilimumab. Given the foregoing, we attempted to investigate FKBP5 splicing during T lymphocyte activation and assess its role in Treg formation and suppression capability. We found that FKBP5 splicing occurred early in the course of a suboptimal but not maximal PBMCs stimulation. The increase in FKBP51s was transient and associated with a delay in Akt and STAT5 activation. When splicing was prevented, Treg count was decreased and Tconv cell proliferation increased. Moreover, measure of FKBP51s level in Foxp3CD25high Treg subset showed highest levels in PBMCs cultures under suboptimal CD3 co-stimulation. Coculture suppression assays showed that Treg silenced for FKBP51s had a significantly reduced suppressive capability, compared with non-silenced Tregs. In conclusion, our findings suggest that FKBP5 splicing occurs under conditions of suboptimal CD3 co-stimulation of Tconv cells and concurs to their differentiation into Tregs. Manipulating FKBP5 splicing can be a means to control tumor tolerance.