PIAS3 suppresses acute graft-versus-host disease by modulating effector T and B cell subsets through inhibition of STAT3 activation

Graft-versus-host disease (GVHD) caused by transplanted donor T cells remains the major obstacle of allogeneic bone marrow transplantation (BMT). Previous reports have suggested that IL-17-producing helper T (Th17) cells mediate the development of acute GVHD (aGVHD). Protein inhibitor of activated STAT3 (PIAS) inhibits the activity of the transcription factor STAT3, which is a pivotal transcription factor for Th17 differentiation. To elucidate whether PIAS3 could inhibit the development of aGVHD, pcDNA-PIAS3 or mock vector was administered in a murine model of aGVHD by intramuscular injection and subsequent electroporation. The results demonstrated that PIAS3 overexpression by pcDNA-vector administration significantly attenuated the clinical severity and histopathological severities of aGHVD involving the skin, liver, intestine, and lung. Additionally, the STAT3 activities in aGVHD target organs were suppressed by PIAS3 overexpression. Furthermore, phosphorylated (p) STAT3 activity in the spleen was profoundly attenuated in PIAS3-overexpressing GVHD mice. Interestingly, flow cytometric analysis demonstrated that the populations of CD21^highCD23^low marginal zone B cells were dramatically expanded in PIAS3-overexpressing mice. PIAS3-induced inhibition of aGVHD was largely related to the downregulation of Th1 and Th17 and the upregulation of Th2 and Treg populations. Both populations of pSTAT3^Tyr705-expressing Th17 cells and B cells were significantly reduced in the spleens of PIAS3-overexpressing mice, whereas pSTAT5 activity was increased. In addition to CD4⁺CD25⁺Foxp3⁺ Treg cells, the populations of CD8⁺CD25⁺Foxp3⁺ Treg cells were also expanded by treatment with PIAS3. These data suggest the therapeutic potential of PIAS3 in the development of aGVHD through reciprocal regulation of Th17/Treg lineages.