PIM kinases regulate early human Th17 cell differentiation

The serine/threonine-specific Moloney murine leukemia virus (PIM) kinase family (i.e., PIM1, PIM2, and PIM3) has been extensively studied in tumorigenesis. PIM kinases are downstream of several cytokine signaling pathways that drive immune-mediated diseases. Uncontrolled T helper 17 (Th17) cell activation has been associated with the pathogenesis of autoimmunity. However, the detailed molecular function of PIMs in human Th17 cell regulation has yet to be studied. In the present study, we comprehensively investigated how the three PIMs simultaneously alter transcriptional gene regulation during early human Th17 cell differentiation. By combining PIM triple knockdown with bulk and scRNA-seq approaches, we found that PIM deficiency promotes the early expression of key Th17-related genes while suppressing Th1-lineage genes. Further, PIMs modulate Th cell signaling, potentially via STAT1 and STAT3. Overall, our study highlights the inhibitory role of PIMs in human Th17 cell differentiation, thereby suggesting their association with autoimmune phenotypes. [Display omitted] •IL6/STAT3 axis promotes PIM expression in human Th17 cells•PIMs inhibit Th17 differentiation•PIMs suppress Th17 TF RORA while promoting Th1 TF TBX21 within the same cells•Specific downstream targets of PIMs negatively influence Th17 cell differentiation Buchacher et al. show that the three PIM kinases inhibit early human Th17 cell differentiation, by suppressing key Th17 -related genes while promoting the expression of Th1 lineage-specific genes. PIMs control this Th1/Th17 axis, potentially via the STAT family proteins, STAT1 and STAT3, suggesting their involvement in inflammatory phenotypes.