LKB1 isoform expression modulates T cell plasticity downstream of PKCθ and IL-6

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• CD4 T cells differentiate into various T helper (Th) cell subsets, a process involving metabolic and transcriptional changes.
• T cell plasticity, particularly between regulatory T (Treg) and Th17 cells, is observed in inflammatory conditions like colitis, driven by cytokines such as IL-6.
• PKCθ promotes Th17 differentiation and inhibits Treg differentiation, while LKB1 (encoded by Stk11) is crucial for Treg survival and function.

Purpose of the Study:

• To investigate the role of Stk11 splice variants in T helper cell differentiation.
• To elucidate the signaling pathway regulating Stk11 splicing in response to IL-6.
• To understand the mechanisms underlying T cell plasticity, specifically iTreg to Th17 cell conversion.

Main Methods:

• Utilized siRNA to deplete hnRNPLL in Th17 cells.
• Analyzed Stk11 splicing patterns and expression of its variants.
• Investigated the regulatory role of PKCθ in hnRNPLL and Stk11 splicing.

Main Results:

• hnRNPLL mediates the splicing of Stk11 into its short variant (Stk11_S) in Th17 cells.
• Depletion of hnRNPLL reduced Stk11_S expression.
• PKCθ regulates hnRNPLL and consequently Stk11_S expression in Th17 cells.
• IL-6 exposure induced Stk11 splicing downstream of PKCθ in both Th17 cells and developing iTregs.

Conclusions:

• A novel IL-6-initiated signaling pathway involving PKCθ and hnRNPLL regulates Stk11 splice variants, promoting Th17 differentiation.
• This pathway also operates in iTregs exposed to IL-6, providing mechanistic insight into iTreg plasticity and conversion to Th17 cells.
• The findings reveal a new mechanism for controlling T cell phenotype stability and plasticity.