STAT5 polarization promotes iTregs and suppresses human T‐cell alloresponses while preserving CTL capacity

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: allogeneic hematopoietic stem cell transplantation;    GVHD;    alloreactivity;   

DOI  :  10.1189/jlb.0313154

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

AlloreactivitynegativelyinfluencesoutcomesoforgantransplantationorHCTfromallogeneicdonors.StandardpharmacologicimmunesuppressionimpairsT‐cellfunctionandjeopardizesthebeneficialreconstitutionofTregs.MurinetransplantationmodelshaveshownthatSTAT3ishighlyexpressedinalloreactiveTcellsandmaybetherapeuticallytargeted.TheinfluenceandeffectsofSTAT3neutralizationinhumanalloreactivity,however,remaintobeelucidated.Inthisstudy,S3I‐201,aselectivesmall‐moleculeinhibitorofSTAT3,suppressedhumanDC‐allosensitizedT‐cellproliferationandabrogatedTh17responses.STAT3blockadesignificantlyenhancedtheexpansionofpotentiTregsandpermittedCD8+cytolyticeffectorfunction.Mechanistically,S3I‐201polarizedtheratioofSTATphosphorylationinfavorofSTAT5overSTAT3andalsoachievedasignificantdegreeofFoxp3demethylationamongtheiTregs.Conversely,selectiveimpairmentofSTAT5phosphorylationwithCAS285986‐31‐4markedlyreducediTregs.STAT3representsarelevanttargetforachievingcontroloverhumanalloresponses,whereitssuppressionfacilitatesSTAT5‐mediatediTreggrowthandfunction...

【 授权许可】

CC BY