sa-4-1bbl costimulation inhibits conversion of conventional cd4+ t cells into cd4+foxp3+ t regulatory cells by production of ifn-γsa-4-1bbl聚集有关抑制转换传统的cd4 + t细胞cd4 + foxp3 + t调节细胞ifn-γ的生产.pdfVIP

SA-4-1BBL Costimulation Inhibits Conversion of Conventional CD4+ + + T Cells into CD4 FoxP3 T Regulatory Cells by Production of IFN-c Shravan Madireddi, Rich-Henry Schabowsky, Abhishek K. Srivastava, Rajesh K. Sharma, Esma S. Yolcu*., Haval Shirwan*. Institute for Cellular Therapeutics, Department of Microbiology and Immunology, and James Brown Cancer Center, University of Louisville, Louisville, Kentucky, United States of America Abstract + + + + Tumors convert conventional CD4 T cells into induced CD4 CD25 FoxP3 T regulatory (iTreg) cells that serve as an effective means of immune evasion. Therefore, the blockade of conventional CD4+ T cell conversion into iTreg cells represents an attractive target for improving the efficacy of various immunotherapeutic approaches. Using a novel form of 4-1BBL molecule, SA-4-1BBL, we previously demonstrated that costimulation via 4-1BB receptor renders both CD4+and CD8+ T effector (Teff) cells refractory to inhibition by Treg cells and increased intratumoral Teff/Treg cell ratio that correlated with therapeutic efficacy in various preclinical tumor models. Building on these studies, we herein show for the first time, to our ¨ + 2 knowledge, that signaling through 4-1BB inhibits antigen- and TGF-b-driven conversion of naıve CD4 FoxP3 T cells into iTreg cells via stimulation of IFN-c production by CD4+ FoxP32 T cells. Importantly, trea