PKCq modulates LKB1 isoforms downstream of IL-6 signaling to mediate iTreg-Th17 cell plasticity

Abstract

Abstract Following activation, CD4 T cells undergo metabolic and transcriptional changes responding to external cues and differentiate into T helper (Th) cells. This differentiation process was perceived to be terminal. However, it has been shown that T cells exhibit plasticity between subsets in highly inflammatory environments. This phenomenon is prevalent in autoimmune conditions, such as colitis, in which high levels of IL-6 promote plasticity between regulatory T (Treg) cells and Th17 cells. Protein Kinase C theta (PKCq) is a serine/threonine kinase that promotes Th17 differentiation while negatively regulating Treg polarization. The tumor suppressor liver kinase B1 (LKB1) encoded by Stk11, a serine/threonine kinase, enforces energy-preserving mechanisms such as fatty acid oxidation, a major energy source for Tregs. Recent studies demonstrate loss of LKB1 disrupts Treg survival and function. Stk11 can be alternatively spliced into a short variant by the inclusion of a cryptic exon. However, specificity of LKB1 isoforms influencing Th plasticity has not been elucidated. Our study shows that the expression of the Stk11 short splice variant (Stk11S) is upregulated in Th17 compared to induced (i)Tregs. We demonstrate that, in Th17 cells heterogeneous ribonucleoprotein L-like (hnRNPLL), a splicing factor promoting cryptic exon inclusion, binds to transcripts of Stk11 and correlates with increased expression of Stk11S. We further show in iTregs exposed to IL-6, Prkcq, Stk11S, and Rorc are upregulated, suggesting iTreg-Th17 plasticity is induced in response to IL-6 resulting in Stk11 splicing downstream of PKCq. Thus, PKCq may destabilize iTreg programming through its regulation of Stk11 splicing under pro-inflammatory conditions. Supported by grants from the department of defense.